Crosstalk Between the Spleen and Other Organs/Systems: Downstream Signaling Events

Abstract

The aim of this review was to gather pieces of information from available critically evaluated published articles concerning any interplay in which the spleen could be involved. For many years, the spleen has been alleged as an unnecessary biological structure, even though splenomegaly is an objective finding of many illnesses. Indeed, the previous opinion has been completely changed. In fact, the spleen is not a passive participant in or a simple bystander to a relationship that exists between the immune system and other organs. Recently, it has been evidenced in many preclinical and clinical studies that there are close associations between the spleen and other parts of the body, leading to various spleen–organ axes. Among them, the gut–spleen axis, the liver–spleen axis, the gut–spleen–skin axis, the brain–spleen axis, and the cardio-splenic axis are the most explored and present in the medical literature. Such recent sources of evidence have led to revolutionary new ideas being developed about the spleen. What is more, these observations may enable the identification of novel therapeutic strategies targeted at various current diseases. The time has come to make clear that the spleen is not a superfluous body part, while health system operators and physicians should pay more attention to this organ. Indeed, much work remains to be performed to assess further roles that this biological structure could play.

1. Introduction

Should we expand the horizons of how we look at the spleen? For a long time, the spleen has been reckoned as a useless organ, even though in clinical practice its increased volume is a hallmark of various diseases. On the other hand, functional hyposplenism, so called when there is a low performance of this organ, leads patients to an overwhelming risk of infections. This consequence is due to the fact that the spleen is one of the focal points of activity of the reticuloendothelial system and can be contemplated as equivalent to a large lymph node. In this regard, a drastic reduction in its function, as determined by splenectomy, is associated with impaired immunoglobulin production, antibody-mediated clearance, and phagocytosis, all of them escalating the risk of sepsis [1]. These events should be taken into serious consideration, as post-splenectomy infection is burdened by high mortality.

As a central immune organ, the spleen has been identified by compelling observations not only as a site for storage but also for the rapid spread of monocytes, recognizing splenic monocytes as a resource that the body utilizes to modulate inflammation [2]. Furthermore, following deep studies about its organization and structure, the spleen has been considered a major hematopoietic organ [3]. In this regard, (99 m) Tc-labeled, heat-altered, autologous erythrocyte scintigraphy with multimodality single-photon emission computed tomography technology is the best tool to evaluate splenic function [4]. The main functions of the red pulp consist of the elimination of old, damaged, and dead red blood cells, along with antigens and microorganisms; release of antigen-specific antibodies synthesized by plasma cells into the circulation; antibacterial protection by using the iron metabolism of its macrophages; sequestration of platelets; and extra-medullary hematopoiesis. In the cords of the sub-capsular portion, there is an “assemblement” in clusters of reservoir monocytes (distinct from macrophages and dendritic cells). The functions of the white pulp are storage for B and T lymphocytes; synthesis of complement, opsonins, properdin, and tuftsin, necessary for the clearance of bacteria; development of B and T lymphocytes upon antigenic challenge; and delivery of immunoglobulins following antigenic challenge by B lymphocytes. The functions of the marginal zone comprise screening the blood for foreign molecules and phagocytosis of circulating microorganisms and immune complexes by macrophages. The volume and weight of the spleen generally differ, with larger spleen size detected in men compared with women and in taller individuals. A normally sized spleen measures up to 12 cm in cranio-caudal length. A length superior to 12 cm indicates splenomegaly, and a length greater than 20 cm is definitive of huge splenomegaly [5]. Coming back to the enlarged volume of the spleen, the most frequent origins of this organ modification are blood disorders, autoimmune diseases, inherited metabolic disorders, viral infections, liver disease, cancer, venous thrombosis, congestive heart failure, focal lesions, cysts, and abscesses.

Table 1. Common causes of splenomegaly.

Hemolitic Anemia and Neutropenia

Lupus Erythematosus and Adult-Onset Still’s Disease

Sarcoidosis and Rheumatoid Arthritis

Niemann–Pick Disease

Gaucher Disease and Sickle Cell Disease

Acute Viral Hepatitis, Mononucleosis, and HIV

Bacterial Endocarditis and Tuberculosis

Malaria, Leishmaniasis, and Toxoplasmosis

Chronic Hepatitis and Cirrhosis

Leukemia and Myeloproliferative Neoplasms

Lymphomas and Metastatic Cancer

summarizes them.

Scholars have established that there are important links between the spleen and other organs of the body, leading to various spleen–organ axes. The present study sets out to look at how the spleen, beyond being an immune “sentinel”, is intertwined with other parts of the body. On this subject, we have surfed PubMed, Scopus, Embase, Research Gate, and Scholar, aiming to gather data concerning these interactions. Data resulting from available preclinical and clinical studies have shown biological communications between the spleen and distant organs based on a two-way pathway.

2. Spleen Axes

2.1. Gut–Spleen Axis

Gut mucosal bacteria are engaged in the development and maturation of the spleen in the way that the presence of a more similar microbiota with a higher characterization of pathogenic species gives place to a fast replenishment of the marginal zone and the IgM plasma cell compartment of the spleen in concert with a decrease in IgA plasma cells in the gut [6,7]. What is more, gut microbiota can be useful for improving the spleen function, especially in those spleens disarranged by a disease or an anti-cancer treatment. Hence, a contemporary study has established that alginate oligosaccharide-improved gut microbiota can save the anticancer drug busulfan-disrupted spleen vasculature and the splenic function, fostering its immune cells and acting on iron metabolism [8]. Antibiotic therapy in mice caused a reduction of interferon (IFN)-gamma, interleukin (IL)-17, IL-22, and IL-10 by CD4+ cells in both splenic and small/large intestinal districts; this synthesis could, at least in part, be restored upon fecal microbiota transplantation (FMT) [9]. Recent findings suggest that splenectomy leads to an atypical composition of the gut microbiota with important shifts of lactic acid and n-butyric acid levels compared with those of control (no surgery) and sham-operated mice [10]. The relevance of the previous study is sustained by the findings that butyrate dramatically improves the number and function of mucin-secreting goblet cells by inducing the polarization of intestinal macrophages towards M2 type, with a consequent increase in intestinal barrier repair [11]. Considering the relationships among short chain fatty acids (SCFAs) and the spleen, via metabolic alterations, it is reasonable that SCFAs generated by gut microbiota can start and maintain the immune responses involved in the carbon metabolism, including the methionine and folate cycles. Specifically, findings support an active role for the microbiota in boosting the CD8+ T cell long-term survival as memory cells and suggest that microbial metabolites steer the metabolic adjustment of activated CD8+ T cells in order to allow this transition in the spleens of germ-free mice [12]. It is worth stressing that depletion of obligate anaerobes, stemming from antibiotics, can modify the use and subsequent metabolism of microbiota-derived SCFAs by colonocytes [13].

2.2. Liver–Spleen Axis

The research topic with a major scientific impact concerning the liver–spleen axis deals with nonalcoholic fatty liver disease (NAFLD), recently renamed metabolic dysfunction-associated steatotic liver disease (MASLD). Of note, when comparing the reliability of the old acronym with the new one, authors found that 99% of patients with NAFLD met MASLD criteria [14].

What is striking is the fact that the intestinal dysbiosis alters the gut permeability [15]. These modifications play an influential role in the development of liver diseases [16]. Coming back to antibiotics, their widespread use not only in humans but also in animals has given place to residues in derived foods, such as milk and dairy products. These antibiotic residues influence human gut flora, putting in motion a chain of events that leads directly to various metabolic alterations that may finally contribute to the onset and progression of NAFLD [17]. In keeping with the previous findings, new insights seek to ameliorate the management of metabolic dysfunction-associated steatohepatitis (MASH) identified Bacteroides uniforms strains as effective producers of 3-succinylated cholic acid (3-sucCA), both in vitro and in vivo. 3-sucCA, a lumen-restricted metabolite, is negatively related to hepatic injury in patients with liver-tissue-biopsy-proven metabolic-associated steatohepatitis (MASH) [18].

Interestingly enough, the main aspect of this tie-up, is that the spleen provides an extra monocyte reservoir in inflammatory conditions of the hepatic tissue. Precisely, CD11b + CD43 hi Ly6C lo splenic monocytes move into the liver and switch to macrophages, which elucidate the exacerbation of the hepatic fibrosis [19]. The afore-mentioned histological feature is peculiar to advanced liver damage, as in the case of liver cirrhosis. The spleen is constantly involved in this stage, due to portal venous hemodynamic changes, resulting in its increased volume. In turn, the spleen impacts the liver cirrhosis progression by modulating hepatic fibrogenesis, inducing immune microenvironment dysregulation, and ultimately by leading to liver regeneration [20]. As a consequence, the spleen is determinant when evaluating decompensation events, better defined as acute-on-chronic liver failure, in patients with spontaneous portosystemic shunting, mainly in the presence of splenorenal shunts [21,22]. Dealing with the non-cirrhotic portal hypertension, idiopathic portal hypertension (IPH) is a disease of unknown etiology, characterized by splenomegaly and hypersplenism with pancytopenia. In this context, splenectomy should be considered as a foremost therapeutic choice for IPH [23]. Both splenectomy and partial splenic artery embolization (PSE) were matched with the prevention of secondary sarcopenia in 45 patients with liver cirrhosis by evaluating the skeletal muscle index (SMI) along a five-year follow-up. Specifically, between the splenectomy/PSE group and the non-treatment one, with regard to levels of ammonia and myostatin, as well as of SMI, significant differences were shown [24]. By the way, sarcopenia is related to the evolution of acute-on-chronic liver failure in decompensated liver cirrhosis patients receiving trans-jugular intrahepatic portosystemic shunt [25]. Again, sarcopenia is associated with a poor prognosis in patients with splenic abscess presenting to the emergency department [26].

Approaching immune system-based diseases, trypanosomiasis is a classical infection causing intense inflammatory responses in the hepatic tissue [27]. In an experimental murine model of this parasitosis, researchers found a remodeling of the spleen compartment represented by the emptying of several lymphocyte populations, enrollment of T-cell-mediated immune suppression, mobilization of monocyte/macrophage cell populations, and finally by the modification of the neutrophil compartment [28]. This study once again offers new challenges and results in substantial shifts from thinking of the spleen as part of the circulatory system towards a significant immune organ. Splenomegaly was linked to the more severe liver inflammation in a primary biliary cholangitis murine model, with both liver mononuclear cell infiltration (histological score of hepatic inflammation) and bile duct damage directly correlated to the degree of splenomegaly. Again, this effect was set back by the quadruple antibiotic treatment [29]. Similarly, liver damage is common in COVID-19 patients due to the cytokine storm triggered by the virus and as a consequence of hypoxia. The spleen impairment in these patients consists in the architectural derangement of the B cell compartment, accompanied by white pulp atrophy and decrease in or absence of lymphoid follicles, while the IgM memory B cell pool is profoundly reduced [30].

Returning to the main issue, Tsushima et al. were the first investigators who showed, by computed tomography, that the increment in spleen volume was commonly seen in patients with NAFLD [31]. Successively, researchers found that the cut-off of the spleen longitudinal diameter at ultrasonography (US), a solid measure of organ volume that best discriminated patients with the more severe form of NAFLD, i.e., MASH, from simple fatty liver, was 116 mm (specificity 95% and sensitivity 88%) [32]. Trying to elucidate the mechanisms underlying the spleen enlargement found in a significant percentage (38%) of female Sprague-Dawley rats fed a high-fat diet (HFD) by the Cavalieri stereologic volume calculation method (an objective stereological method), authors hypothesized that HFD leads to splenomegaly via sinusoidal dilatation and intra-cellular or intercellular deposits [33]. Pieces of research have already pointed towards a link between basal metabolic rate (BMR) and NAFLD [34]. Successive data showed a link between the hepatic growth factor, secreted by mesenchymal cells normally located under the splenic capsule [35], and BMR mediated by IL-16 [36]. Using the “from neck-to-knee” magnetic resonance imaging (MRI), clear patterns showed that men, younger subjects and individuals with type 2 diabetes mellitus (T2DM) and NAFLD had a larger spleen compared with females, older subjects and controls, respectively. The enlarged spleen observed in NAFLD could mirror an increased portal venous pressure taking place already in its early stage [37]. Scholars, studying a predictive system to ascertain nonalcoholic steatohepatitis (NASH, renamed MASH), evidenced that it is possible by adopting the following parameters: Attenuation of the echo amplitude, presence of focal fat sparing, and enlarged splenic diameter [38]. Surprisingly, a study in 275 patients enrolled between 2015 and 2019 with biopsy-proven NAFLD evidenced no correlation between splenomegaly and the severity of liver damage, hypothesizing a substitute mechanism for splenomegaly, i.e., raised deposition of lipid in the spleen [39]. In line with all the discoveries presented above concerning NAFLD/MASLD, there is much debate around the liver–spleen axis, nor are results uniform, even though using the spleen longitudinal diameter at US as a new marker for evaluating the spleen volume could be a simple, cheap and largely available tool [40].

Heavy metals, a topic that we shall deepen successively, can pollute the environment and are commonly found in the diet (such as fruits and vegetables, milk and dairy products, meat and meat derivatives, oils, and alcoholic beverages) [41]. In adequate amounts, heavy metals are essential nutrients for maintaining good health, but in larger quantities, they become threatening for many organs, due to oxidative stress induced by free radical formation [42]. Chronic oral exposure to needless amounts of copper can be hepatotoxic according to LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [43]. Captivating pieces of research highlighted that excessive copper intake can be also immunotoxic, giving place to spleen damage and overproduction of inflammatory cytokines. Remarkably, copper sulfate (CuSO₄) induced apoptosis by increasing TUNEL-positive cells in the spleen of mice. At the same time, CuSO₄ increased the mRNA levels of IL-1beta, IL-2, IL-4, IL-6, IL-12, tumor necrosis factor-alpha, and IFN-gamma. In addition, CuSO4 decreased the activities of antioxidant enzymes, such as superoxide dismutase, catalase and phospholipid hydroperoxide glutathione peroxidase, reduced total glutathione contents, and increased malondialdehyde contents. Finally, CuSO₄ enhanced the expression of newly phosphorylated protein, gamma-H2AX, which is the marker of DNA damage [44]. Recent studies confirmed that sublethal exposure to copper (as copper chloride) causes toxicity in the spleen and augments the sub G₀/G₁ population among splenocytes, again suggesting apoptosis, which is mediated, to a certain extent, by the EndoG-Bax-ubiquitin pathway [45]. On the other hand, copper insufficiency also can be dangerous. An entrancing aspect concerns the association of copper status with NAFLD, as a proportion of NAFLD patients suffering from this disease are considered copper deficient [46]. Consistent with the prior observation, high fat intake, potentiated by an excess of fructose in the diet, alters in rats the energy metabolism (lowering liver glucose-6-phosphate dehydrogenase) and worsens the nutritional benefit of copper, ultimately inducing a deficiency of this metal [47]. Current evidence indicates that low copper bioavailability leads to increased hepatic iron stores due to a decrease in ferroportin expression and ceruloplasmin ferroxidase activity, with a consequent block of liver iron export [48]. Excess liver iron is one of the main subsequent molecular processes leading to enhanced rates of steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma [49]. It should be underlined that oxidative stress is a factor contributing to the progression of NAFLD, while antioxidant molecules such as silymarin, silybin or silibinin, pentoxifylline, resveratrol, vitamins A, C, and E are potential therapeutic agents against NAFLD [50]. Recent data show that impaired copper bioavailability foretells early atherosclerosis in obese patients with hepatic steatosis detected by US, i.e., NAFLD [51]. This main cardiovascular (CV) risk will be dealt with below.

2.3. Gut–Spleen–Skin Axis: What Does Psoriasis Have to Do with This Connection?

The gut–skin axis indicates the bidirectional relationship between the gut microbiome and skin health [52]. Now, a possible mediation of the spleen is explored. First of all, traditional Chinese medicine considers spleen deficiency as an important basis of intestinal microecological disorder. Symptoms of psoriasis in patients with spleen deficiency are more prolonged and difficult to alleviate, being prone to recurrence [53]. As recently reviewed, inflammation paves the way for the downstream molecular events of psoriasis, focusing on the most specific cytokine circuit, i.e., IL-17, beyond tumor necrosis factor (TNF)-alpha and IL-23 [54]. The spleen tyrosine kinase (SYK) is an important regulatory molecule of signal transduction pathways related to the onset and progression of autoimmune diseases. The activity of SYK, which is consistent with the transcription level of SYK, is much higher in the spleen than in other tissues [55]. A recent study evaluated the effects of an SYK inhibitor (R406) on imiquimod (IMQ)-induced psoriasis-like inflammation. Authors evidenced that R406 brings about the attenuation of IMQ-induced dermal inflammation. The effect was simultaneous, with the reduction in CD11c+ (marker of dendritic cells), IL-6, IL-23, major histocompatibility complex II, and CD40 (cluster of differentiation). As a consequence, there was a suppression of Th17 cells and an up-regulation of Treg cells in R406-treated mice [56]. Surprisingly, splenectomy did not impact IMQ-induced psoriasis-like phenotypes compared with sham-operated mice, even though splenectomy augmented the expression of IL-17A mRNA in the skin of IMQ-treated mice [57]. The involvement of the spleen in this very common skin disease was ascertained by a case study that showed a correlation between the spleen volume, measured at US as longitudinal diameter, and the duration of psoriasis [58]. A successful experiment, crossing KCASP1Tg mice with IL-17A knockout mice to generate IL-17A-/KCASP1Tg, showed a severe amyloid deposition in the spleen. Amyloidosis is a serious complication of inflammatory skin disease [59].

That said, doubts on the role of the spleen in psoriasis persist, making the issue highly debatable. Nevertheless, we should try to look into the matter from another point of view, i.e., linking “co-morbid systemic diseases” to psoriasis, following the IL-17 pathway that has been ascertained to modulate the inflammatory responses [60].

2.4. Relationship Between Psoriasis and Psoriasis-Associated Illnesses: Is There Any Role of the Spleen?

Patients with psoriasis have a higher risk of “single and multiple organ-based co-morbidities” than the general population, such as, but not only, cerebrovascular accidents (CVA) [61], as will be evidenced below. As a case in point, one intriguing clinical study, by quantitatively analyzing the splenic 18F-fluorodeoxyglucose uptake as an index of systemic inflammation, evidenced an increment of splenic inflammation in patients with moderate-to-severe psoriasis compared to control subjects. Moreover, and this is very attractive, authors documented that splenic inflammation is associated with aortic inflammation, supporting an interconnection between the spleen and atherosclerotic plaques in patients with psoriasis [62].

Intriguingly, the gut microbiota is estimated to be a central factor in the development of inflammatory bowel disease (IBD) and, contextually, psoriasis. IBD and psoriasis patients show an impaired intestinal microbiome characterized by a decrease in Faecalibacterium Prausnitzii, and by an increase in Escherichia coli. Faecalibacterium Prausnitzii is not only one of the most copious determinants of butyrate, secreting anti-inflammatory molecules that regulate the host immune system, but also an inducer of T regs [63]. A recent study performed in 90 patients with Crohn’s disease (CD), who underwent 188 computed tomography (CT) exams over 6 years, showed that the splenic size was augmented in patients with CD compared with that in normal individuals [64]. A concomitant investigation evidenced that not only was the spleen volume, evaluated by CT and adjusted for the body weight, significantly increased in patients with CD compared to the controls, but also strongly correlated with the CD activity. Indeed, the authors had a suspicion that the inflammatory cells and cytokines entered the blood vessels and exerted a marked influence on the spleen due to the breakdown of the intestinal tract barrier in CD [65]. On the other hand, IBD is closely associated with NAFLD, with up to one-third of patients with IBD experiencing NAFLD worldwide [66]. These results were confirmed by a report evidencing that NAFLD was highly prevalent in a cohort of German IBD patients, with 48% of CD patients suffering from NAFLD [67]. In a population-based cross-sectional study that included 5672 US adults from 20 to 59 years of age, psoriasis was associated with NAFLD in adjusted models [68]. Again, and contrary to the prevailing opinion, about 15–40% of patients with IBD are obese [69]. Similarly, there seem to be important links between obesity and NAFLD [70]. In line with the latter findings, patients with metabolic syndrome (MS) had spleen sizes larger than those of healthy controls, and this was significantly related to waist circumference [71]. On the other hand, treatment approaches for IBD (steroids) may cause adverse hepatic effects. In a case series, it was evidenced that they could foster weight gain and contribute to the development of NAFLD [72]. Therefore, patients with IBD on this type of hormonal substance should be constantly monitored for the development of NAFLD [73]. NAFLD and irritable bowel syndrome (IBS) are canonically judged as distinct diseases. It has long been established that NAFLD is associated with MS, while IBS is generally considered a functional intestinal illness, frequently associated with psychological disorders such as depression and anxiety. Indeed, many aspects are shared by both diseases, such as the intestinal dysbiosis, the impaired intestinal barrier, and the altered intestinal motility, which are central to their genesis and continuation, all of them being related to the immune activation and inflammation [74]. As evidenced in a recent meta analysis, the proportion of NAFLD subjects with IBS increased with NAFLD severity [75]. Authors suggest that the microbiota could mediate both the structural composition and partitioning of the spleen immune cells by modulating the expression levels of chemokines [76]. These connections of various distant organs would close the circle of the gut–skin–spleen–liver.

2.5. Central/Peripheral Nervous System–Spleen Axis: The Intricate Network

One thorough review collects strong evidence of a direct connection between the brain and the spleen, in the sense that the spleen regulates the humoral immune defense by activating two brain regions, recognizing corticotropin-related neurons in the paraventricular nucleus and the central nucleus of the amygdala. Also, afferent and efferent vagus nerve signaling may contribute to communication between the brain and spleen [77]. A solid proof of the central nervous system (CNS)–spleen axis relies upon improved clinical outcomes in patients with severe burn injuries, by coordinating multiple signaling pathways (including sympathetic and parasympathetic pathways). A better prognosis is due to the recovery of the immune imbalance following the burn-induced hypermetabolic response and associated sepsis complications [78]. Indeed, the spleen plays a role in the immune system not only through the brain–spleen axis but also via microbiota modification, labeled by the authors as the gut–microbiota–spleen–brain axis. In keeping with the antecedent results [29], one treatment with an antibiotic cocktail (ABX) for 14 days resulted in a significant decrease in the spleen weight and significant alterations in splenic functions, including the percentage of neutrophils, NK cells, macrophages, and CD8+ T cells. As expected, the ABX treatment ended up depleting a significant amount of the gut microbiota [79]. These data, on the one hand, present corroborating evidence of the dynamic communications that exist between the gut bacteria and body defenses, but on the other, show that the effect of antibiotic-induced changes in gut bacteria populations on host immunity depends on the starting bacteria composition. Recent findings indicate that the sympathetic spleen denervation attenuates both the infiltration of hematopoietic cells into the paraventricular nucleus of the hypothalamus and pulmonary hypertension (PH) development, indicating that hematopoietic cells contribute to lung inflammation as well as to the dysfunctional neuro–immune axis observed in PH [80]. This observation is important in view of the fact that PH is a frequent consequence of obstructive sleep apnea, hypoventilation syndrome, the use of anorexigenic agents, cardiomyopathy, and pulmonary thromboembolic disease, each of them linked to obesity [81]. In this context, it is worth recalling that the gut microbiome is a well-recognized factor in the pathophysiology of obesity [82]. The aforementioned connection between lungs and the spleen is confirmed by results from a novel investigation challenging the mediastinal lymph node paradigm. This piece of research shows that, during influenza virus infection, lung migratory dendritic cells escape the mediastinal lymph nodes and traffic to the spleen, where they prime influenza-specific CD8+ T cells. CD8+ T cells primed in the spleen are transcriptionally distinct and have an enhanced ability to differentiate into long-lived memory cells [83].

Approaching the vagal–spleen axis, captivating findings reveal that this network influences the white adipose tissue (WAT) mass in the healthy state, while it seems to be altered in hypothalamic (again) obese animals. Specifically, vagotomy promotes body weight and adiposity reduction, elevating IL-10 plasma levels in non-obese animals in a “spleen-dependent manner”. Vice versa, in rats with hypothalamic obesity, vagal nerve ablation reduces body weight gain and adiposity, improving insulin sensitivity, but without changes in the IL-10 expression in WAT or IL-10 plasma levels, and in a “spleen-independent manner” [84]. Both the gut microbiota–vagus nerve axis and gut microbiota–spleen axis have a prominent roles in modulating systemic inflammation induced by sleep deprivation after liposaccharide administration [85]. Recent results still emphasize the vagus nerve–spleen anti-inflammatory axis, in the sense that this connection is engaged in increasing the postprandial glucagon-like peptide (GLP)-1 response after Roux-en-Y gastric bypass in T2DM rats. Splenic denervation eliminated the increase in postprandial GLP-1 levels in response to the mixed-meal challenge, led to higher TNF-alpha levels in the spleen (as well as in the ileum) and down-regulated the splenic alpha 7 nicotinic acetylcholine receptor, implicated in long-term memory, compared with denervated sham rats [86]. As a collateral but fundamental observation, the vagus nerve relays signals also between the liver and brain, regulating peripheral adiposity and pancreas function. For that reason, scientists have observed that neuronal signals via the hepatic vagus nerve contribute to the development of NASH and to the protection against obesity in HFD-fed Pemt⁻/⁻ mice [87].

An intriguing aspect, dealing with stress, zeroes in on the brain–spleen connection. Firstly, stress leads to an imbalance of neural circuitry supplying cognition, decision-making, anxiety and mood, in turn affecting systemic physiology via neuroendocrine, autonomic and metabolic mediators [88]. The adverse effects of the repeated exposure to stress are widely known to have deleterious effects on health. Mechanisms underlying adaptive and maladaptive changes involve brain plasticity [89]. But, “strain” bears a more important impact on the immune system. Accordingly, the authors showed that in mice, the spleen contributes to the alteration of the restraint stress-induced distribution of blood leukocytes. In particular, they evidenced that chronic restraint stress (CRS) decreased the CD4/CD8 ratio and elevated the percentages of natural killer cells, monocytes and polymorphonuclear myeloid-derived suppressor cells [90]. Psychological stress-induced responses promote tumor progression and have a large impact on the spleen. At this end, recent data indicate that CRS promotes hepatocellular carcinoma growth and suppresses the antitumor immunity of tumor-bearing mice. Splenectomy could inhibit tumor growth and partly block the decrease in antitumor immune activity induced by stress [91]. Recent experiments suggest that CRS could induce lung injury and CD11b+Ly6ChiLy6G- monocytes aggregation in the lung. Additionally, splenic CD11b+ cells might play an important role in CRS-induced lung injury [92]. Stress may also increase weight gain and fat deposition, modifying feeding behavior. Chronic stress is known to modify the pattern of food intake, dietary preference, and the rewarding properties of foods [93]. We know that any stressful experience activates distinct neuronal circuits in the brain and leads to multiple changes at the cellular level [94]. Surprisingly, the splenic nerve plays a role in inflammation-related depression and in the microglial activation of the hippocampus via gut microbiota, affecting the brain via the gut–microbiota–spleen axis [95]. And, it always ends up with the spleen as a crucial player.

2.6. Heart–Kidney–Spleen Axis: The Involvement in a Life-Treatining Disease

There is also abundant proof of the cardio–splenic axis being central to downstream signaling events of ischemic heart failure. Researchers have discovered that mice with ischemic heart failure show robust expansion of proinflammatory monocytes/macrophages, classical and plasmacytoid dendritic cells. In this context, there is a profound splenic remodeling, indicative of an increased antigen processing and expansion of both antigen-experienced effector and memory CD4+ T cell populations [96]. Assessing the fate of monocytes linked to ischemic injury following acute myocardial infarction (AMI), scholars showed consecutive interconnections with the endothelium and other immune cells, thus creating a complex interplay between monocytes and the cardiac milieu [97].

In particular, monocytes (CD14(+) cells), with their populations CD14(+)CD16(−) and CD14(+)CD16(+), accumulated in the human myocardium following AMI. That phenomenon coexists with a pronounced depletion of monocytes from the spleen [98]. The mobilization of spleen-derived polymorphonuclear-myeloid-derived suppressor cells (MDSCs), promoted by an increased A2B adenosine receptor (A2BAR) mRNA expression, is another immune event in AMI. As a matter of fact, the circulating MDSC ratio was higher in AMI patients. Similarly, in AMI model mice, it was evidenced that the percentage of MDSCs was increased in both the circulation and infarcted heart and decreased in the spleen. A2BAR blockade consequently hampered the myocardial cell apoptosis, attenuated the myocardial inflammatory injury, and raised the myocardial systolic function.

Contrarily, spleen-derived MDSC injection expanded the myocardial cell apoptosis, worsened the myocardial injury, and lessened the cardiac systolic function in the former animal model [99]. Ticagrelor, a platelet aggregation inhibitor, co-administered with acetylsalicylic acid and indicated for the prevention of atherothrombotic events in adults with acute coronary syndromes or a history of AMI, still increases the percentage of M-MDSCs in the circulation and infarcted heart of AMI mice in a dose-dependent manner, attenuates the cardiac inflammation and augments the cardiac contractile function [100]. Stimulating findings using 18F-fluorodeoxyglucose-positron emission tomography imaging in 508 individuals across two studies evidenced increased splenic metabolic activity after acute coronary syndrome and highlighted an association with proinflammatory remodeling of circulating leukocytes. What is more, the authors of this study perceived that the metabolic activity of the spleen independently predicted risk of subsequent CV disease events [101]. Common mechanisms linking heart failure and splenic activation embrace a functional remodeling of the spleen, larger release of immune cells from the spleen, chronic pro-inflammatory response, and finally, a cardiac remodeling that consists in both positive (suppression of inflammation in myocardial tissue environment) and negative outcomes (increased cardiac fibrosis). On the other hand, heart failure with worsening cardiac function leads to hemodynamic changes and neurohormonal activation, with the subsequent adjustment of circulating blood volume throughout one of the main splenic functions, i.e., that of the blood volume reservoir, which ultimately gives place to the structural remodeling of the spleen [102].

To date, few pathways have convincingly connected the spleen to the kidney. In a mouse model of septic kidney injury, dexmedetomidine, an alpha-adrenergic agonist used to manage pain and sedation, but also a potent inhibitor of the inflammatory response [103], by itself reduced apoptosis in kidney tissue; on the contrary, apoptosis increased after splenectomy in mice treated with this non-opioid drug. Splenectomy decreased circulating proinflammatory cytokines and had a protective effect on the kidney, by inhibiting the dexmedetomidine-mediated activation of the alpha7-nicotinic acetylcholine receptor, a key protein in the cholinergic anti-inflammatory pathway that links the nervous and immune systems [104]. The spleen axes are evidenced in Figure 1.

3. Discussion

A fascinating field of investigation is the relationship of the spleen to hormones. As a historical curiosity, the hypothesis that the spleen can function as an endocrine organ was formulated a long time ago [105]. In the present day, there is a vast consensus on the necessity of not considering the spleen an endocrine organ, lacking the synthesis and release of hormones.

At the same time, it was clearly seen that the spleen underpins a close connection with specific hormones. In support of this opinion, changes in the volume and weight of the spleen are instrumental in driving a functional rearrangement, which in turn modifies specific functions. This fits neatly with data from a recent investigation that bears witness to the lower insulin-like growth-1 status being associated with increased spleen longitudinal diameter, higher fat mass (determined by bioelectrical impedance analysis), c-reactive protein levels and more severe hepatic steatosis, according to liver hyperechogenicity [106]. In a light and electron microscopic study, the effects of hormones, i.e., estrogen and progesterone, on the spleen of gonadectomized male mice were assessed using quantitative methods. Estrogen led to an increase in the weight of the spleen. Both red and white splenic pulps were significantly enlarged, with the red one markedly increased in volume [107]. Still, the spleen–thyroid relationship is not new; as early as 1927, hyperthyroidism was reported in medical contexts to be associated with an increased spleen volume, and at the same time, splenomegaly was employed as a diagnostic tool [108]. It is ascertained that leukocytes are rapidly recruited to the pre-ovulatory ovary and play a crucial role as facilitators of ovulation and the luteal formation. In this context, the authors explored the novel hypothesis that the hypothalamus–pituitary–ovary axis might comprehend the spleen as a reservoir [109]. Further deepening the morphological events that link the spleen to hormones, it is noteworthy that the removal of the hypophysis in adult rats was followed by the progressive atrophy of the spleen. In this context, hypophysectomy completely inhibited the regeneration of splenic tissue after partial splenectomy [110]. Indeed, testosterone has been described as affecting the cellularity of the spleen [111]. Incubation of cells in medium with 0.8 × 10⁻⁵ M testosterone generated a small decrease in the splenocyte viability, similarly to that observed with 17 beta-estradiol in cultured mouse splenocytes. Moreover, there was a marked reduction in the percentage of viable cells (70%) when splenocytes were incubated with 0.5 × 10⁻⁵ M dexamethasone [112]. Male mice lacking the androgen receptor have increased splenic B cell numbers, serum levels of B-cell activating factor (BAFF), also known as tumor necrosis factor ligand superfamily members, and splenic Baff mRNA. Testosterone deficiency by castration causes the expansion of BAFF-producing fibroblastic reticular cells in the spleen [113]. Previous analysis evidenced that both bisphenol and the pharmaceutical 17alpha-ethinyl estradiol have dose- and sex-specific impacts on the cellular and microanatomical structures of the spleen, showing alterations in immunomodulatory and hematopoietic functions [114]. Surprisingly, researchers reported a second case of insulinoma arising from the heterotopic pancreas and the first to originate from an intrasplenic heterotopia [115]. Still, in relation to glucose metabolism, we should mention a study conducted to weigh the impact of whey proteins (WPs) on the spleen tissues of diabetic rats. WPs restored the oxidative stability and splenic structural integrity and activity. The authors suggested these natural products for the treatment of T2DM and oxidative stress [116]. The relationship may be complex and context-dependent, involving various factors such as genetics, diet, and lifestyle. However, further studies are needed to fully understand the role of hormones in the development and progression of endocrinopathies linked to spleen modifications.

Melatonin is a hormone secreted by the “enigmatic” pineal gland in response to darkness, but not exclusively, being also produced by lymphocytes and macrophage under IFN-gamma stimulation [117], and is associated with longevity [118]. The weight of the spleen was prone to increase in a former study in “active” rats on melatonin at doses of 0.5 and 1 mg/kg. After stress exposure, the relative weight was reduced, suggesting that melatonin regulates both the hemodynamics and function of the spleen as a stress-marker organ [119]. A twelve-week oral melatonin treatment (10 mg/kg/day, far larger doses than those generally used for humans) raised sarcolipin (SLN) protein levels in the vastus lateralis in both obese and lean adult male rats [120]. We know that SLN, highly expressed during aging, elevates intracellular calcium overload and cooperates in the impaired myogenic differentiation. Therefore, targeting SLN could represent a novel therapeutic strategy to alleviate sarcopenia-associated muscle fibrosis [121], a condition common to many diseases [122]. Accordingly, as previously reported [24], it can be expected that muscle volume loss is reduced by splenectomy.

Aging is associated with changes that result in increased susceptibility to and frequency of disease or disability, and is characterized by the following hallmarks: genomic instability, telomere dysfunction, epigenetic alterations, loss of proteostasis, compromise of autophagy, and mitochondrial dysfunction [123]. Among downstream molecular events, the following are therefore of the utmost interest for our topic. Fibroblast Growth Factor 23 (FGF23), regulating vitamin D metabolism, is electively expressed in bone tissues, but the spleen contributes significantly to increasing its circulating levels in response to lipopolysaccharide-induced inflammation [124]. Vitamin D deficiency is associated with an high risk of age-related chronic diseases and consequently shortens the lifespan [125]. Concerning longevity, Klotho is a transmembrane protein controlling insulin sensitivity and is involved in life expectancy. Lower plasma levels of α-klotho in older adults are linked to increased frailty and to all-cause mortality [126]. On this basis, the FGF23–Klotho signaling axis is thought to exercise anti-aging effects via calcium–phosphorus metabolism. Interestingly, in mice deficient in FGF23–Klotho signaling, the number of splenocytes is reduced [127]. On top of that, a fascinating question concerns the link between the following signaling protein family and the spleen. Sirtuins (SIRT) are essential factors for postponing aging and increasing the longevity of organisms. They act in regulating the function of various cellular processes, such as intermediate metabolism, oxidative stress, apoptosis, and inflammation [128]. Intriguing studies show that SIRT and Klotho interact with each other at different levels of gene expression and signaling pathways [129]. For example, the knockdown of SIRT6 blocked the ameliorating effect of Klotho on the heart, leading to the conclusion that, by SIRT6 mediation, Klotho impacts the mammalian target of the rapamycin signaling pathway and averts cardiomyopathy [130]. Researchers, using Western blot, showed that SIRT6 was widely expressed in different tissues, with a particularly strong expression in the spleen, beyond that of the thymus and intestines [131]. Additionally, SIRT6 regulates lifespan in male mice [132]. The spleens of SIRT2/3⁻/⁻ mice contained 17% less CD11c+ DCs and 39% less Ly6G+ granulocytes in comparison to their levels in bone marrow [133]. Mitochondrial SIRT4 determines a type of immune tolerance in monocytes by realigning glycolysis and glucose oxidation homeostasis, thus acting as a physiologic contributor to acute inflammatory resolution [134]. Recently, some studies have demonstrated the involvement of SIRT4 in age-related processes [135], down-regulating the insulin secretion by beta cells in response to amino acids [136], thus counteracting the pro-aging effect of insulin [137]. Notably, the clinical significance of the SIRT4/AMPKalpha/p53/autophagy axis was demonstrated in human pancreatic ductal adenocarcinoma specimens. Taken together, these findings suggested that SIRT4 induced autophagy, a hallmark of aging [138]. Surprising data showed that the FOXQ1–SIRT4–glutamate dehydrogenase axis is a new target for improving human longevity; FOXQ1, a forkhead family transcription factor, is important for the preservation of SIRT4 expression levels in juvenile cells [139]. Interestingly, SIRT4 over-expression in splenic naive Treg cells was found to alleviate the expression of FOXP3, another member of the FOX family, also called scurf, and of IL-10 and also the transforming growth factor beta, contextually impairing the inhibitory activity of Treg cells. Furthermore, SIRT4 overexpression blocked inducible Treg cell generation from conventional T cells in vitro [140]. The aforementioned findings are consistent with the hypothesis that mitochondrial SIRT4 governs the axis that controls anabolic and catabolic energy sources, determining immune tolerance in monocytes [134]. It is pleonastic to stress that the spleen is the storage organ for monocytes. What is compelling is that larger spleens were associated with higher insulin resistance [141]. Hyperinsulinemia and the concomitant insulin resistance are related to an increased risk of age-related diseases leading to a shortened lifespan [137].

Strikingly, not surprisingly though, there is also a muscle–spleen axis, apart from the spleen’s involvement in sarcopenia. Using a genetic mdx-4cv mouse model of dystrophinopathy to study Duchenne muscular dystrophy, typified by ongoing muscle wasting due to deficiency in the membrane cytoskeletal protein dystrophin, biochemical and proteomic analyses identified that the mdx-4cv spleen showed a significant proteome-wide increase in tissue transglutaminase, highly resistant to proteolysis, and matrix metalloproteinase-9, as well as a great decrease in E and B apolipoproteins engaged in metabolism, signaling and cellular architecture [142]. Finally, connecting the spleen with the locomotor apparatus, patients with rheumatoid arthritis, systemic lupus erythematosus, and polyarteritis nodosa are at risk of experiencing a spontaneous splenic rupture [143].

The scale of threats to the biosphere and its lifeforms, not to mention humanity, has been growing faster in recent decades [144]. Involved researchers have long prided themselves on being at the cutting edge of forecasting the noxious effects of environmental changes. Encompassing climatic fluctuations, ocean acidification, land degradation, water scarcity, overexploitation of fisheries and biodiversity loss, they have determined serious health effects due to highly impartial, disorganized, and unsustainable patterns of resource consumption and technological development, coupled with population growth [145]. Climate change is already affecting the health of millions of people all over the world [146]. Could environmental factors have a burden on the spleen? The answer is unfortunately positive, at least lending credence to preclinical studies. In utero heat stress decreases growth commensurate with that of calves born to cooled dams, characterized by immune organs particularly threatened [147]. The problem with such findings is that differentiating between correlation and causation is not straightforward—that is to say, identifying broadly simultaneous warming patterns on the one hand and organ structural changes on the other is not the same as proving that the former was responsible for the latter.

4. Future Directions

Likewise, we face many man-made environmental poisons, such as heavy metals found in water and food, toxins residing in building materials and air toxins detected indoors or outside. Actually, the burden of diseases from these environmental risks is becoming increasingly unsustainable [148]. A precise exposure assessment is of importance for risk estimation. We should point out that within research focusing on natural hazards, the questionnaire is a fundamental tool for acquiring information [149]. Indeed, questionnaire-based data could introduce misclassification and recall bias. Lifestyle factors (e.g., smoking) or nutritional factors may confound the association. Thus, the observational study design in this specific field has an inherent partiality. With these premises, even though animal experiments allow the separate administration of suspected agents, their toxicological value is limited by low exposure levels in many of today’s settings and failure to investigate gene–environment interactions [150].

Micro/nanoplastics pollution is one of the most daunting problems for human health, experts say. That is because the microscale particles occupy cells and tissues, impairing cellular processes and depositing endocrine-disrupting molecules such as bisphenols (BPAs), phthalates, flame retardants and heavy metals [151]. In chicken, authors evidenced the impact of polystyrene microplastics on the spleen, resulting in the expansion of the white pulp, as well as programmed death (apoptosis and ferroptosis), and showed the regulative role of mitochondria in this injury [152]. Very recent data on the avian spleen, with the aid of the Japanese quail (Coturnix japonica) as animal model,, are illustrative of the fact that microplastics lead to ultrastructural changes in splenocytes, such as membrane lysis and mitochondrial vacuolation, signs of inflammation. This status is confirmed by increasing concentrations of proinflammatory cytokines, i.e., TNF-alpha, IFN-gamma, IL-1 beta, and IL-6, and decreasing levels of the anti-inflammatory cytokine IL-10. Contextually, reactive oxygen species and malondialdehyde increased, and superoxide dismutase, catalase and glutathione S-transferase were switched off, suggesting oxidative stress in the spleen [153]. Histopathological features of BPA-treated mice showed toxicity, with significant changes in active germinal centers of the white pulp coupled with the scarcity of apoptotic cells. At the same time, eosinophils and lymphocytes invaded the red pulp in a significant manner [154]. The increasing use of pesticides year after year has paved the way for finding high levels of residual pesticides in the aquatic environment, as in the case of difenoconazole (DFZ). The DFZ exposure induces apoptosis, immunosuppression, oxidative stress, and inflammatory responses in the spleen tissue of carp, damaging this organ [155]. Due to increasing amounts of metals in the environment, authors using light microscopy found a modified morphology of the spleen tissue, consisting in tissue necrosis, in male Sprague-Dawley rats exposed to cadmium, chromium and mercury [156]. Human activities generate significant amounts of particulates. The PM2.5-induced metabolic changes in the spleen could, to a greater extent, exacerbate the adverse effects of HFD on mice, resulting in a hampered splenic metabolism of lipids [157]. Nanoparticles of anatase titanium dioxide (extensively used in plastics, ink, coatings, paper, rubber, chemical fiber, chemical, ceramics, pharmaceuticals, food, and some industries), after oral exposure in a rat model, were detected in the spleen as a target organ for bioaccumulation, with increased white pulp in the group of high-dose females [158]. The triangulation of epidemiology, animal studies, and deep investigations into the biosphere points convincingly to the conclusion that the spleen is an organ with multiform functions, overall maintaining the immune balance and eliciting a rapid and consistent response to external noxious stimuli. While it is important to note which organs and systems have a connection with the spleen, such as the gut, liver, heart, SNC, skin, muscle and kidney, it is also worth paying attention to the ones with which the spleen does not have a connection—above all, but not limited to, the sense organs. In fact, more advanced study is required to establish whether the spleen could have a function in digestion, given that the spleen phylogenetically and embryologically interconnected with the endodermal stomach parenchyma [159].

5. Captivating Trends

While there is extensive evidence showing a close association between environmental factors and obesity, the supposed causal relationship is less striking. It has been reported that increases in global BMI have equated with the augmented population in cities, prompting the conviction that urbanization is a main driver of the global rise in obesity [160] due to its influence on physical activity levels [161]. It should be stressed that the diagnostic accuracy of BMI to assess the incidence/prevalence of obesity is limited, especially in the intermediate BMI ranges in men and in the elderly [162]. But, a recent systematic review and meta-analysis showed that for metabolic syndrome/obesity (MS/O), the performances of the waist-to-height ratio, BMI, and waist circumference were comparable [163]. Dealing with patients with MS/O, one recent clinical investigation showed in those subjects a spleen size increased compared to that of the healthy controls [71]. One future field of research will address the role of the spleen in physical activity, whose increase is a beneficial approach to MS and its components [164]. Exercise results in hemoconcentration, which is generally attributed to a reduction in plasma volume [165]. Is there any capacity to autotransfuse an amount of red blood cells from the spleen into the active circulation? According to comparative research carried out in several athletic mammalian species, human spleen could account for 30% of the increase in hematocrit [166]. As a consequence, proper function of the spleen is necessary for safe physical activity. On the other hand, considering that diabetes-related spleen damage leads to immune dysfunction, resulting in increased risks of infection in diabetic patients, a direct spleno-protective action could be desirable. Accordingly, one interesting study in diabetic rats treated with hesperidin showed that this flavanone glycoside, found in citrus fruits, regulates Bcl-2 family proteins and inhibits the oxidative stress and inflammatory status of hyperglycemia-mediated spleen apoptosis [167]. A very recent network meta-analysis showed that alcohol abuse can damage the spleen, impacting white pulp and red pulp morphology, increasing splenocyte apoptosis and reducing splenocyte proliferation, thus altering the immune function [168]. This area of investigation is particularly important for the health care system, in the light of excessive alcohol exposure among youngsters [169]. New perspectives point out how impaired splenic function influences more than one-third of adult patients with celiac disease, predisposing to a higher risk of bacterial infection and autoimmune complications, such as ulcerative jejunoileitis and enteropathy-associated T-cell lymphoma [170]. It is necessary to stress the great impact that SARS-CoV-2 infection has on health, because it not only induces pulmonary lesions but also affects extrapulmonary organs like the spleen and lymph nodes (LNs), beyond different segments of the alimentary tract, kidney, adrenal gland, and ovary. The importance of secondary lymphoid organs, such as the spleen and LNs, in opposing infection is well delineated. Tissue-resident macrophages placed in the splenic marginal zone are among the first cell types to rise against invading pathogens [171]. The resident macrophages of the subcapsular sinus and hilar LNs have been suggested to function in a protective role against viral infections by taking up viral particles [172]. Interesting findings have shown that lymphocytopenia is prevalent in patients with COVID-19 [173]. In conformity with the histological features, the levels of viral RNA, and the antigen distribution observed in humans with COVID-19, authors noticed a white and red pulp depletion with a diminution in the follicle number and size in infected hamsters [174].

The restoration of the gut microbiota to a healthy state using FMT is gaining increased interest; this procedure is beneficial for treating severe infections by inducing the eradication of multidrug-resistant organisms [175]. The safety of FMT in immunocompromised patients, such as those that have undergone splenectomy, needs to be established. Periodontal diseases are prevalent both in developed and developing countries and affect about 20–50% of the global population [176]. Porphyromonas gingivalis (P. gingivalis), a primary perio pathogen determining the origin and development of periodontal disease, is associated with NASH [177]. Administrated P. gingivalis greatly induced the production of the interferon (IFN) regulatory factor and activated the inflammatory pathway IFN-gamma/STAT1 in the spleen of mice presenting with a spleen index markedly higher relative to controls [178]. By the way, P. gingivalis causes a systemic inflammatory response and disrupts insulin signaling pathways, leading to insulin resistance [179]. Accordingly, fascinating studies have identified a group of spleen-supplied innate-like B cells in visceral adipose tissue as participants in curbing the insulin-antagonizing environment during obesity and have pointed to these cells as new targets for therapeutic intervention in obesity-associated inflammation and insulin resistance [180]. In dealing with bariatric surgery, examining the spleen dimensions via ultrasound gastroscopy prior to surgery could avoid probable complications, as enlarged spleen size limits the surgeon’s working area, and because leaks often occur in the upper part of the stomach adjacent to the spleen [181]. An interesting new role of the spleen is emerging in fundamental pharmacokinetic processes of new-generation drugs, such as monoclonal antibodies, nanoparticles and exosomes [182]. An interconnection between the heart, spleen, and bone marrow in the background of heart failure with a preserved ejection fraction, based on extramedullary hematopoiesis in the spleen, has been recently suggested. This viewpoint could lead to an attractive therapeutic approach to heart failure [183]. Stroke is a severe disease with high mortality. Both the central and peripheral inflammation, including the activation of resident and peripheral immune cells, lead to an interplay between the spleen (beyond gut, heart and lung) and the brain after ischemic stroke [184]. Platelets are key factors in the hemostasis and regulation of inflammatory responses in acute and chronic lung injury. Platelets in the lung are derived from the spleen, beyond the bone marrow. Obviously, it is of great significance to explore this aspect in the treatment of lung injury (especially lung cancer) [185].

Finally, as a promising diagnostic tool, spleen stiffness measurement (SSM) provides a non-invasive surrogate marker for diagnosing clinically severe portal hypertension, even though in real-world practice, sound SSM values were obtained only in 70% of cases [186]. Volumetric analyses of the liver and spleen by abdominal CT and MRI provide important prognostic information due to the reliability in stratifying the stage of hepatic fibrosis and disease severity [187].

6. Conclusions

The gathered data leave little room for doubt about the centrality of the spleen, and lead to the emphatic conclusion that this organ, collectively, plays a central role in the homeostasis of many species’ organism. Certainly, there are wide ranges of connections between the spleen and other parts of the body, as well as networks with different systems. In other words, there is no “one size fits all”, but rather considerable nuance depending on the specific function of this prominent organ, nor are responses always identical, given that the role of the spleen is more complicated and more varied than has long been thought. Not surprisingly, eye-catching arguments in this “arena” are and will be a matter of lively discussion and sometimes heated debate among scientists, because they voice particular concerns about the problems of distinguishing between association and causation. Nevertheless, altered connections between the spleen and other organs support a new possible interpretation of diseases in the sense that crosstalk is not just an important factor but a fundamental element that underpins the health and well-being at every stage of one’s life. Further explorations should be performed in order to understand the role of the spleen in the so-called diseases of affluence and other health conditions for which personal lifestyles and ambient conditions represent important risk factors. It is high time for physicians to think of the spleen as a pivotal organ in the human body.