Search Results (18)

Chronic musculoskeletal pain and sarcopenia co-occur at rates exceeding epidemiological independence in older adults. However, no systematic review has examined whether exercise-induced myokine signaling suppresses shared NF-κB–driven inflammatory pathways to concurrently address chronic pain and sarcopenic muscle loss in older adults. Following PRISMA 2020 guidelines, we searched PubMed, Web of Science, Scopus, and Embase (January 2000–March 2026) and included 32 studies (RCTs, cohort, cross-sectional, and mechanistic designs) in adults aged ≥45 years with chronic musculoskeletal pain and/or sarcopenia; studies lacking an exercise component or human mechanistic relevance were excluded, and findings were qualitatively synthesized. The included studies suggest that persistent NF-κB hyperactivation—driven by SASP, LPS–TLR4 signaling, and mitochondrial ROS—is associated with both sarcopenic muscle loss and pain sensitization. Evidence from included studies indicates that contracting skeletal muscle secretes IL-6, IL-15, irisin, BDNF, and myostatin, which were frequently associated with suppression of NF-κB activity, attenuation of NLRP3 inflammasome activation, and improvement in pain inhibition—suggesting a hypothesized shared mechanistic pathway that awaits direct validation in trials enrolling older adults with co-confirmed sarcopenia and chronic pain. Multicomponent training emerged as the modality most consistently associated with concurrent benefits for both conditions across included studies. The synthesized evidence supports considering a two-phase approach—pain neuroscience education followed by progressive resistance training—as a hypothesis-driven framework to improve exercise adherence and myokine responses. These findings suggest that myokine signaling represents a plausible shared mechanistic pathway linking exercise to concurrent improvements in sarcopenia and chronic pain, warranting direct validation in future trials. Full article

Butyrophilin-like 2 (BTNL2) is an immunomodulatory molecule critically involved in regulating the host immune response to infection with the avirulent Mycobacterium tuberculosis strain H37Ra. However, its functional role in modulating pyroptosis and associated inflammatory responses remains incompletely characterized. Here, we demonstrate that BTNL2 deficiency exacerbates pyroptosis and the inflammatory response in H37Ra-infected murine peritoneal macrophages via two distinct pathways. First, the loss of BTNL2 induces excessive mitochondrial damage, which leads to aberrant release of mitochondrial DNA (mtDNA) and accumulation of mitochondrial reactive oxygen species (mtROS), thereby triggering NLRP3 (NOD-like receptor family pyrin domain containing 3) inflammasome activation and gasdermin D (GSDMD)-mediated pyroptosis. Second, cytosolic mtDNA accumulation hyperactivates the cGAS–STING signaling axis, resulting in transcriptional upregulation of NLRP3 and consequent amplification of pro-inflammatory cytokine production. Collectively, these findings demonstrate that BTNL2 acts as a regulator of mitochondrial homeostasis and innate immune balance during H37Ra infection in primary peritoneal macrophages. The results provide mechanistic insights into BTNL2 function in the context of H37Ra-induced pyroptosis. Full article

Background/Objectives: Chronic low-grade inflammation, underpinned by persistent activation of the NLRP3 inflammasome, is a central pathological mechanism in non-communicable diseases including cardiovascular disease, type 2 diabetes, inflammatory bowel disease, and neurodegeneration. Dietary polyphenols have been consistently associated with reduced inflammatory burden; however, the mechanisms underlying these effects remain incompletely understood. This review aims to characterize the gut microbiota–polyphenol–NLRP3 inflammasome axis as a central regulatory network through which diet modulates innate immune signaling and chronic inflammatory tone. Methods: A comprehensive narrative review of the available literature was conducted, integrating evidence from mechanistic studies in cell culture and animal models, microbiome research, metabolomics, and human epidemiological and interventional data. Results: The gut microbiota emerges as a critical biochemical intermediary that transforms dietary polyphenols into bioactive metabolites, including urolithins, phenyl-γ-valerolactones, protocatechuic acid, and short-chain fatty acids, with enhanced bioavailability and potent inflammasome-modulating properties. These compounds suppress NLRP3 activation through multiple converging mechanisms, including inhibition of NF-κB-dependent priming, mitochondrial quality control via mitophagy, Nrf2-mediated antioxidant responses, and HDAC inhibition. Evidence across cardiovascular, metabolic, neurological, and respiratory disease models supports the translational relevance of this axis. Conclusions: The microbiota–polyphenol–NLRP3 axis functions as an integrated, self-regulated network in which each component simultaneously shapes and is shaped by the others: dysbiosis primes NLRP3 and depletes protective metabolites, while inflammasome hyperactivation further destabilises microbial ecology; polyphenol biotransformation by specific taxa interrupts this feed-forward loop at multiple nodes, restoring homeostasis. Full article

Cigarette smoking is the leading preventable cause of chronic diseases (e.g., COPD, cardiovascular disease, cancer), largely driven by persistent immune-inflammatory mechanisms. This review synthesizes the molecular and cellular cascades linking cigarette smoke (CS) exposure to chronic pathology. CS constituents, particularly ROS/RNS, induce rapid oxidative stress that overwhelms antioxidant defenses and generates damage-associated molecular patterns (DAMPs). These DAMPs activate pattern recognition receptors (PRRs) and the NLRP3 inflammasome, initiating NF-κB signaling and the release of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6). CS exposure causes profound innate immune dysregulation, including airway epithelial barrier disruption, hyperactivated neutrophils, and dysfunctional alveolar macrophages (AMs) that release destructive proteases (e.g., MMP-12) and acquire foam-cell–like characteristics. Furthermore, CS drives adaptive immunity toward a Th1/Th17-dominant phenotype while suppressing regulatory T-cell (Treg) function, thereby promoting autoimmunity and chronic tissue injury. Critically, CS induces epigenetic reprogramming (e.g., DNA methylation, miRNA dysregulation), locking immune cells into a persistent pro-inflammatory state. This convergence of oxidative stress, innate and adaptive immune dysregulation, and epigenetic alterations underlies the systemic low-grade inflammation that fuels smoking-related chronic diseases, highlighting key targets for novel therapeutic interventions. Full article

Background: Familial cold urticarias (FCU) are a group of rare hereditary disorders triggered by exposure to low temperatures. Their pathogenesis is complex, involving mast cell activation, inflammasome dysregulation, and abnormalities of the kallikrein–kinin system. This review aims to summarize the genetic classification, molecular mechanisms, and clinical implications of FCU in diagnosis and management. Methods: Recent literature was reviewed to outline the clinical and molecular characteristics of familial atypical cold urticaria (FACU), familial cold autoinflammatory syndromes (FCAS; including NLRP3-, NLRP12-, NLRC4-, and PLCG2-related subtypes), FXII-associated cold autoinflammatory syndrome (FACAS), and familial predisposed acquired cold urticaria (FP-ACU). Mechanistic clues and diagnostic strategies were analyzed, emphasizing the integration of clinical features with molecular findings. Results: Distinct FCU subtypes exhibit defined genetic bases: gain-of-function mutations in NLRP3, NLRP12, and NLRC4 result in inflammasome hyperactivation; in-frame deletions in PLCG2 lead to temperature-dependent immune signaling dysregulation; and heterozygous F12 variants link contact activation with inflammatory cascades. Combining cold stimulation tests, inflammatory biomarkers, and targeted genetic sequencing enables precise molecular stratification. Conclusions: Molecular subclassification of FCU improves diagnostic accuracy and informs targeted therapy. Future research should focus on the interplay between cold-sensing ion channels, mast cell activation, and inflammasome signaling to advance precision diagnosis and individualized treatment of cold-induced urticarias. Full article

Coxsackievirus B3 (CV-B3) infection causes inflammatory conditions such as viral myocarditis and meningitis, and incidence rates are rising annually. While children are more likely to be affected by severe manifestations, the molecular basis of this age-dependent susceptibility is poorly understood. In this study, we used young Balb/c mice at three developmental stages (7-, 14-, and 30-day-old mice) to investigate CV-B3 pathogenesis. Our findings revealed that 7-day-old mice exhibited substantial infection susceptibility and pathological severity compared to older mice. Critically, an age-dependent analysis showed a progressive decline in the expression of CV-B3-binding Coxsackievirus and Adenovirus Receptor (CAR) splice variants (CAR1 and CAR2) at both the transcriptional and translational levels as the mice matured from 7 to 30 days. These receptor isoforms demonstrated a direct correlation with viral replication efficiency in younger hosts. Concurrently, aging was associated with a rise in non-binding CAR variants (CAR3 and CAR4). During CV-B3 infection, the abundance of CAR1/CAR2 in young mice facilitated accelerated viral proliferation, coupled with the hyperactivation of the NLRP3 inflammasome and the expansion of IL-17-producing γδT cells (γδT17 cells). This cascade triggered excessive production of proinflammatory cytokines (IL-1β, IL-18, and IL-17), culminating in pronounced inflammatory infiltrates within cardiac and cerebral tissues. These findings establish NLRP3 inflammasome dysregulation as a critical determinant of CV-B3-induced tissue damage and provide novel insights into the heightened susceptibility to CV-B infection during early life and its associated severe disease rates. Full article

Inflammation assumes a vital role in the pathogenesis of depression and in antidepressant treatment. Paeoniflorin (PF), a monoterpene glycoside analog possessing anti-inflammatory attributes, exhibits therapeutic efficacy on depression-like behavior in mice. The objective of this study was to evaluate the antidepressant effects of PF on depression elicited by the chronic unpredictable mild stress (CUMS) model and the precise neural sequence associated with the inflammatory process. In this study, we established an in vivo mouse model induced by CUMS and an in vitro BV2 cell model induced by LPS+ATP. The mechanism of PF for depression was assessed by the SIRT1 selective inhibitor EX-527. The findings demonstrated that PF significantly alleviated the damage of BV2 cells treated with LPS and ATP, inhibited the generation of ROS, up-regulated the expression of SIRT1 mRNA, and down-regulated the expression of nuclear NF-κB, p65, NLRP3, Caspase-1 and GSDMD-N in vitro. In vivo, PF mitigated the depressive-like behavior induced by CUMS, reduced the number of neurons, and decreased the secretion of pro-inflammatory factors IL-1β, IL-6, and TNF-α in the hippocampus. Immunohistochemical results indicated that PF attenuated CUMS-induced hyperactivation of microglia. Moreover, the expression level of SIRT1 in the hippocampus was augmented, while the protein levels of NF-κB, p65, NLRP3, Caspase-1, IL-1β and GSDMD-N were diminished after PF treatment. Additionally, the selective inhibition of SIRT1 attenuated the therapeutic effect of PF on depression. These results imply that PF possesses antidepressant properties that rely on SIRT1 signaling to regulate NLRP3 inflammasome inactivation. Full article

Colchicine has a number of effects that suggest it may be useful in the treatment of COVID-19. Myeloid cells are a major source of dysregulated inflammation in COVID-19. The hyperactivation of the NLRP3 inflammasome and the subsequent cytokine storm take place precisely inside them and can lead to multiorgan damage and death. NLRP3 inflammasome inhibition has been assessed at micromolar colchicine concentrations which cannot be achieved in serum. However, colchicine has remarkable ability to accumulate intensively in leukocytes, where the cytokine storm is generated. Over 50 observational studies and randomized clinical trials, small randomized non-controlled trials, and retrospective cohort studies were initiated to test its healing effect in vivo, leading to conflicting, rather disappointing results. The WHO gives a “Strong recommendation against” the use of colchicine for COVID-19 treatment. This is because low doses of colchicine are always used, where the concentrations required to inhibit the NLRP3 inflammasome in leukocytes cannot be reached. Considering this, from March 2020, we started the administration of higher doses of colchicine. Our assumption was that a safe increase in colchicine doses to reach micromolar concentrations in leukocytes will result in NLRP3 inflammasome/cytokine storm inhibition. We demonstrated that in 785 inpatients treated with increasing doses of colchicine, mortality fell between two and seven times. Our data, including a large number of COVID-19 outpatients, showed that nearly 100% of the patients treated with this therapeutic regimen escaped hospitalization. In addition, post-COVID-19 symptoms in those treated with colchicine were significantly rarer. As a large number of viruses can overactivate the NLRP3 inflammasome (like seasonal influenza), we are convinced that higher colchicine doses would be useful in these cases as well. Full article

Pre-eclampsia is a harmful and potentially lethal medical condition during pregnancy clinically diagnosed by hypertension and commonly accompanied by proteinuria and multiorgan affections. According to the time of diagnosis, it is differentiated between early-onset (EO-PE) and late-onset preeclampsia (LO-PE). Despite being less dangerous and presenting distinct pathophysiological signatures, LO-PE has a greater prevalence than EO-PE, both having significant consequences on the placenta. Previous works have evidenced that exacerbated inflammation in this organ might play a potential pathogenic role in the development of pre-eclampsia, and there is some preliminary evidence that the hyperactivation of inflammasomes can be related to the altered immunoinflammatory responses observed in the placentas of these patients. However, the precise role of inflammasomes in the placentas of women with LO-PE remains to be fully understood. In this work, we have studied the gene and protein expression of the main components related to the canonical and non-canonical pathways of the inflammasome NLRP3 (NLRP3, ASC, caspase 1, caspase 5, caspase 8, interleukin 1β, and interleukin 18) in the placental tissue of women with LO-PE. Our results show a marked increase in all these components in the placentas of women who have undergone LO-PE, suggesting that NLRP3 inflammasome plays a potentially pathophysiological role in the development of this entity. Future works should aim to evaluate possible translational approaches to this dysregulation in these patients. Full article

Alteration of NLRP3 inflammasome pathway including hyper-activation or exhaustion has been implicated in the pathophysiology of many diseases. Following cell stimulation, aggregation of the ASC protein into a multiprotein complex, the ASC speck, has been proposed as a specific read-out for monitoring NLRP3 inflammasome activation by flow cytometry in clinical samples. So far, only a few papers have described a technique to detect ASC speck formation directly in whole blood without any cell purification, and none included an ex vivo stimulation. The objective of this study was thus to develop a simple and shortened flow cytometry protocol to detect ASC speck formation directly in whole blood including an ex vivo stimulation step. We showed that after red blood cells lysis and removal of the LPS stimulation step, ASC speck formation can be detected in both monocytes and neutrophils from healthy donors directly in nigericin-stimulated whole blood samples. Using samples from four septic shock patients, we showed that this technique allows for the detection of NLRP3 inflammasome exhaustion in clinical samples. This novel shortened and simple whole blood protocol should facilitate day-to-day monitoring of NLRP3 inflammasome activation and exhaustion in both monocytes and neutrophils in clinical studies. Full article

Streptococcus suis (S. suis) is an emerging zoonotic pathogen that can cause multiple diseases, including streptococcal toxic shock-like syndrome (STSLS). The S. suis SC-19 strain could cause NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome hyperactivation, then induce a cytokine storm and STSLS. Although IL-18 is the downstream effector of NLRP3 signaling, the role of IL-18 signaling on STSLS remains to be elucidated. Thus, il18r1 gene knockout mice were constructed and challenged with the SC-19 strain. Alleviated clinical signs and tissue damages, as well as improved survival were observed in il18r−/− mice compared with the WT mice post-SC-19 challenge. Meanwhile, an obvious decrease in the inflammatory cytokine levels in blood was observed in the il18r-/- mice infected with SC-19. Therefore, IL-18, the downstream effector of NLRP3 inflammasome activation, was responsible for the cytokine storm and STSLS development caused by S. suis, suggesting that IL-18/IL-18Rα signaling could serve as a new target for STSLS. Full article

SARS-CoV-2 infection leads to severe lung damage due to pneumonia and, in more severe cases, leads to acute respiratory distress syndrome, or ARDS. This affects the viability of bronchoalveolar cells. An important role in the pathogenesis of these complications is the hyperactivation of the renin-angiotensin-aldosterone (RAA) pathway and induction of cytokine storm that occurs in an Nlrp3 inflammasome-dependent manner. To shed more light on the susceptibility of lung tissue to SARS-CoV-2 infection, we evaluated murine bronchioalveolar stem cells (BASC), alveolar type II cells (AT2), and 3D-derived organoids expression of mRNA encoding genes involved in virus entry into cells, components of RAA, and genes that comprise elements of the Nlrp3 inflammasome pathway. We noticed that all these genes are expressed by lung alveolar stem cells and organoids-derived from these cells. Interestingly, all these cells express a high level of ACE2 that, on the one hand, serves as an entry receptor for SARS-CoV-2 and, on the other, converts angiotensin II into its physiological antagonist, angiotensin 1–7 (Ang 1–7), which has been reported to have a protective role in lung damage. To shed more light on the role of Ang 1–7 on lung tissue, we exposed lung-derived BASC and AT2 cells to this mediator of RAA and noticed that it increases the proliferation of these cells. Based on this, Ang 1–7 could be employed to alleviate the damage to lung alveolar stem/progenitor cells during SARS-CoV-2 infection. Full article

Toxoplasma gondii is a common opportunistic protozoan pathogen that can parasitize the karyocytes of humans and virtually all other warm-blooded animals. In the host’s innate immune response to T. gondii infection, inflammasomes can mediate the maturation of pro-IL-1β and pro-IL-18, which further enhances the immune response. However, how intercellular parasites specifically provoke inflammasome activation remains unclear. In this study, we found that the T. gondii secretory protein, rhoptry protein 7 (ROP7), could interact with the NACHT domain of NLRP3 through liquid chromatography-mass spectrometry analysis and co-immunoprecipitation assays. When expressing ROP7 in differentiated THP-1 cells, there was significant up-regulation in NF-κB and continuous release of IL-1β. This process is pyroptosis-independent and leads to inflammasome hyperactivation through the IL-1β/NF-κB/NLRP3 feedback loop. The loss of ROP7 in tachyzoites did not affect parasite proliferation in host cells but did attenuate parasite-induced inflammatory activity. In conclusion, these findings unveil that a T. gondii-derived protein is able to promote inflammasome activation, and further study of ROP7 will deepen our understanding of host innate immunity to parasites. Full article

The NOD, LRR, and pyrin domain-containing 3 (NLRP3) protein has been established as a central component of the inflammasome and regulates the inflammatory response to a myriad of environmental, microbial, and endogenous danger stimuli. Assembly of the NLRP3 inflammasome results in the cleavage and activation of caspase-1, in turn causing release of the pro-inflammatory interleukins 1-beta and 18. This activation response, while crucial to coordinated innate immune defense, can be aberrantly activated by the likes of cell-free DNA, and cause significant autoimmune pathology. Complications of autoimmunity induced by aberrant NLRP3 inflammasome activation have a great degree of mechanistic crossover with alloimmune injury in solid organ transplant, and stratagems to neutralize NLRP3 inflammasome activation may prove beneficial in solid organ transplant management. This article reviews NLRP3 inflammasome biology and the pathology associated with its hyperactivation, as well as the connections between NLRP3 inflammasome activation and allograft homeostasis. Full article

The outbreak of the coronavirus disease 2019 (COVID-19) began at the end of 2019. COVID-19 is caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and patients with COVID-19 may exhibit poor clinical outcomes. Some patients with severe COVID-19 experience cytokine release syndrome (CRS) or a cytokine storm—elevated levels of hyperactivated immune cells—and circulating pro-inflammatory cytokines, including interleukin (IL)-1β and IL-18. This severe inflammatory response can lead to organ damage/failure and even death. The inflammasome is an intracellular immune complex that is responsible for the secretion of IL-1β and IL-18 in various human diseases. Recently, there has been a growing number of studies revealing a link between the inflammasome and COVID-19. Therefore, this article summarizes the current literature regarding the inflammasome complex and COVID-19. Full article