Search Results (878)

Cytokine storm is a critical driver of acute respiratory distress syndrome and multiple organ failure. Human β-defensin 2 (HBD-2) is the first inducible defensin discovered in human body. Defensin can resist pathogenic microorganisms invading the body through direct bactericidal effect and also modulates acquired immune response. Albumin exhibits immunomodulatory properties and can reduce the level of inflammatory cytokines to improve the systemic inflammatory response. We previously engineered a recombinant fusion protein, DF₂-HSA, comprising two HBD-2 molecules linked to human serum albumin. Here, we evaluated its effect on cytokine storm using a lipopolysaccharide (LPS)-induced cytokine storm murine model (BALB/c athymic mice, female). DF₂-HSA reduced the mortality in cytokine storm murine model and prolonged the retention time of HBD-2 in the body. A Luminex assay showed that DF₂-HSA reduced the production of multiple inflammatory cytokines in cytokine storm murine model. Evans blue staining showed that DF₂-HSA reduced vascular leakage. Transmission electron microscopy showed that DF₂-HSA reduced the lung injury of cytokine storm mice. The pathological results showed that DF₂-HSA alleviated the lung and small intestine damage of cytokine storm mice. In summary, DF₂-HSA effectively inhibits cytokine storms and ameliorates associated tissue damage. Full article

Mycoplasma pneumoniae pneumonia (MPP) is a common respiratory infection characterized by significant inflammatory responses and lung tissue injury. However, the precise immunological mechanisms and temporal dynamics of key cytokines driving pulmonary inflammation in MPP are still unclear. This study aimed to investigate the underlying immunological mechanisms and cytokine dynamics in MPP. We established an acute MPP murine model via intranasal administration of M. pneumoniae. This model recapitulates key features of human MPP, such as robust airway inflammation and cytokine production. Comprehensive analyses were conducted, including histopathology, flow cytometry, and cytokine profiling. Results showed severe inflammatory responses with prominent infiltration of neutrophils and macrophages in lung tissue, whereas monocyte populations were significantly reduced, indicating a shift towards myeloid cell predominance. Notably, 36 cytokines, including pro-inflammatory interleukins (IL-1β, IL-6, IL-17A) and chemokines, were statistically significantly upregulated in bronchoalveolar lavage fluid compared to the normal group, highlighting a cytokine storm associated with lung inflammation and tissue damage. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway analysis further revealed enriched pathways related to cytokine-cytokine receptor interactions and IL-17 signaling, suggesting potential therapeutic targets. In conclusion, this study preclinical provides insights into the innate immune response and cytokine-driven pathology in acute MPP, underscoring the pivotal roles of myeloid cells and pro-inflammatory cytokines. Future research should focus on clinical validation of these findings to assess their translational potential and the exploration of immunomodulatory strategies informed by this model to mitigate MPP severity. Full article

Background: Organ transplant offers patients a second chance at life, yet chronic rejection remains a formidable barrier to long-term success. Unlike the instantaneous storm of acute rejection, chronic rejection is a slow, unremitting process that silently remodels vessels, scars tissues, and diminishes graft function. At the center of this process are macrophages, immune “shapeshifters” that can heal or harm depending on their cues. Methods: This manuscript systematically reviews and synthesizes the current evidence from experimental studies and clinical observations, as well as molecular insights, to unravel how macrophages orchestrate chronic rejection. It travels over macrophage origins alongside their dynamic polarization into pro-inflammatory (M1) or pro-repair yet fibrotic (M2) states. The discussion integrates mechanisms of recruitment, antigen presentation, vascular injury, and fibrosis, while highlighting the molecular pathways (NF-κB, inflammasomes, STAT signaling, metabolic rewiring) that shape macrophage fate. Results: Macrophages play a central role in chronic rejection. Resident macrophages, once tissue peacekeepers, amplify inflammation, while recruited monocyte-derived macrophages fuel acute injury or dysfunctional repair. Together, they initiate transplant vasculopathy through cytokines, growth factors, and matrix metalloproteinases, slowly narrowing vessels and starving grafts. Donor-derived macrophages, often overlooked, act as early sentinels and long-term architects of fibrosis, blurring the line between donor and host immunity. At the molecular level, macrophages lock into destructive programs, perpetuating a cycle of inflammation, vascular remodeling, and scarring. Conclusions: Macrophages are not passive bystanders but pivotal decision makers in chronic rejection. Their plasticity, while a source of pathology, also opens therapeutic opportunities. Emerging strategies like macrophage-targeted drugs, immune tolerance approaches, gene and exosome therapies currently offer ways to reprogram these cells and preserve graft function. By shifting the macrophage narrative from saboteurs to guardians, transplantation medicine may transform chronic rejection from an inevitability into a preventable complication, extending graft survival from fleeting years into enduring decades. Full article

Acute pancreatitis (AP) is a severe inflammatory disorder characterized by a complex molecular pathophysiology involving premature zymogen activation, organelle dysfunction, and systemic immune dysregulation. Current therapeutic strategies remain largely supportive, underscoring the critical need for specific molecular-targeted interventions. Baicalein, a bioactive flavonoid derived from Scutellaria baicalensis Georgi, has emerged as a potent pleiotropic agent. This review comprehensively synthesizes the molecular mechanisms underlying baicalein’s therapeutic efficacy in AP. Its capacity to intercept the pathological cascade at multiple checkpoints is elucidated, from mitigating the initiating cytosolic calcium overload and preserving mitochondrial integrity to suppressing the cytokine storm via the TLR4/NF-κB/MAPK signaling axis. Crucially, baicalein modulates the pancreatic immune microenvironment by driving the phenotypic polarization of macrophages from pro-inflammatory M1 to reparative M2 states and regulating neutrophil dynamics, specifically by inhibiting infiltration and neutrophil extracellular trap formation. Furthermore, its role in orchestrating regulated cell death pathways is highlighted, specifically by blocking pyroptosis and ferroptosis while modulating apoptosis, and its function as a biophysical scavenger of circulating histones and pancreatic lipase to neutralize systemic toxins. Consequently, this review emphasizes the multi-target biological activities of baicalein, providing a mechanistic rationale for its development as a precision therapeutic candidate for AP. Full article

Autoimmune flares are often accompanied by abrupt surges of circulating plasmablasts—short-lived, high-output antibody-secreting cells generated through extrafollicular B-cell activation in response to microbial cues. Three categories of microbial input appear to repeatedly trigger these “plasmablast storms”: latent herpesvirus reactivations (Epstein–Barr virus, cytomegalovirus, human herpesvirus-6, varicella–zoster virus), acute respiratory or gastrointestinal infections including SARS-CoV-2, and chronic oral or gut dysbiosis. Although biologically distinct, these stimuli converge on innate sensing pathways driven by pathogen-associated molecular patterns such as unmethylated CpG DNA, single-stranded RNA, lipopolysaccharide, and bacterial lipoglycans. Through Toll-like receptors and type I interferon signalling, microbial signatures accelerate class switching, amplify inflammatory cytokine milieus, and lower B-cell activation thresholds, enabling rapid plasmablast mobilisation. Dysbiosis further maintains B cells in a hyper-responsive state by disrupting mucosal homeostasis and altering microbial metabolite profiles, thereby reducing the stimulus required to trigger plasmablast bursts. Once generated, these waves of oligoclonal plasmablasts home to inflamed tissues, where chemokine and adhesion landscapes shape their retention during flares. Emerging evidence suggests that such episodic plasmablast expansions promote autoantibody diversification, somatic hypermutation, and epitope spreading, progressively eroding tolerance. This review synthesizes these insights into a unified model in which infections and dysbiosis promote microbe-licensed plasmablast storms that influence the tempo and severity of autoimmune disease. Full article

The COVID-19 pandemic has profoundly affected societies around the world. Although the emergency phase of coronavirus disease 2019 (COVID-19) has ended, the threat it poses remains persistent. This review aims to clarify the mechanisms of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection to support effective management of the disease. A central focus is the host cellular response to the viral infection, with particular emphasis on the role of cytokines. Cytokines play a dual role in antiviral defense: they contribute to the inhibition of viral replication and facilitate the clearance of pathogens, yet dysregulated cytokine responses can result in severe immunopathology. Interferons (type I, type II, and type III) and other cytokines are pivotal in activating intracellular antiviral mechanisms and in orchestrating the recruitment of immune cells through extracellular signaling. Effective immune responses to viral infections are governed not only by primary immune cells—such as dendritic cells, T lymphocytes, and B lymphocytes—but also by the local cytokine milieu shaped by infected and neighboring cells. Given the presence of endogenous inhibitors and autoantibodies in vivo, it is essential to evaluate the functional activity of cytokines in clinical samples. We propose a novel approach to quantify biologically active cytokine levels. Full article

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is associated not only with respiratory illness but also with profound vascular and coagulation disturbances. Long COVID (LC) is characterized by persistent symptoms such as fatigue, dyspnea, cognitive impairment, and palpitations. Mechanistically, SARS-CoV-2 induces direct endothelial injury, promotes a pro-inflammatory cytokine milieu, and activates platelets, leading to immunothrombosis and impaired fibrinolysis. Consequently, patients exhibit microthrombosis, elevated plasma D-dimer, fibrinogen dysregulation, and persistent hypercoagulability. Clinically, this translates into an increased risk of venous thromboembolism, including deep vein thrombosis and pulmonary embolism, as well as arterial thrombotic events such as myocardial infarction and stroke, which may persist months after acute infection. Understanding the interplay between endothelial injury, inflammation, and coagulation is crucial for risk stratification and the development of preventive and therapeutic strategies. We conducted a systematic narrative review of the literature, including human clinical and mechanistic studies identified through PubMed, Scopus and Web of Science up to 30 September 2025. This review synthesizes current evidence on vascular complications in LC, highlighting endothelial dysfunction as a central pathophysiological nexus linking the acute phase of SARS-CoV-2 infection with chronic LC manifestations. Full article

Background and Clinical Significance: Immune checkpoint inhibitors (ICIs) have transformed the management of advanced solid tumors but can trigger severe immune-related adverse events (irAEs). Among the rarest and most life-threatening is hemophagocytic lymphohistiocytosis (HLH), a hyperinflammatory syndrome driven by uncontrolled immune activation. Case Presentation: We report the case of an 80-year-old man with clear cell renal carcinoma with sarcomatoid features who developed secondary hemophagocytic lymphohistiocytosis (HLH) after receiving four cycles of adjuvant pembrolizumab therapy. Following four cycles of immunotherapy, he presented with persistent fever, pancytopenia, hyperferritinemia (>49,000 ng/mL), hypofibrinogenemia, and elevated soluble IL-2 receptor (>7500 U/mL), fulfilling at least five HLH-2004 diagnostic criteria. Despite treatment with high-dose corticosteroids and intravenous anakinra (100 mg every 6 h), his condition rapidly deteriorated, leading to multiorgan failure and death. Discussion: ICI-induced HLH is an exceptional but increasingly recognized irAE, with fewer than 30 pembrolizumab-related cases reported to date. Diagnosis is challenging due to its nonspecific presentation, which can mimic infection, hepatic toxicity, or disease progression. The pathogenesis is believed to involve excessive activation of cytotoxic T cells and cytokine storm. While established pediatric protocols (HLH-94, HLH-2004) guide management, adult cases often require individualized approaches using corticosteroids and cytokine-targeted therapies such as IL-1 or IL-6 blockade. Conclusions: HLH secondary to ICIs should be considered in the differential diagnosis of patients receiving immunotherapy who develop unexplained fever and cytopenia. Early recognition and prompt initiation of immunosuppressive therapy are critical to improving outcomes in this potentially fatal complication. Full article

Background/Objectives: Sepsis-associated liver injury (SALI) is a critical and often early complication of sepsis, defined by distinct hyper-inflammatory and immunosuppressive phases that shape patient phenotypes. Methods: Characterizing these phases establishes a foundation for immunomodulation strategies tailored to individual immune responses, as discussed subsequently. Results: The initial inflammatory response activates pathways such as NF-κB and the NLRP3 inflammasome, leading to a cytokine storm that damages hepatocytes and is frequently associated with higher SOFA scores and a higher risk of 28-day mortality. Kupffer cells and infiltrating neutrophils exacerbate hepatic injury by releasing proinflammatory cytokines and reactive oxygen species, thereby causing cellular damage and prolonging ICU stays. During the subsequent immunosuppressive phase, impaired infection control and tissue repair can result in recurrent hospital-acquired infections and a poorer prognosis. Concurrently, hepatocytes undergo significant metabolic disturbances, notably impaired fatty acid oxidation due to downregulation of transcription factors such as PPARα and HNF4α. This metabolic alteration corresponds with worsening liver function tests, which may reflect the severity of liver failure in clinical practice. Mitochondrial dysfunction, driven by oxidative stress and defective autophagic quality control, impairs cellular energy production and induces hepatocyte death, which is closely linked to declining liver function and increased mortality. The gut-liver axis plays a central role in SALI pathogenesis, as sepsis-induced gut dysbiosis and increased intestinal permeability allow bacterial products, including lipopolysaccharides, to enter the portal circulation and further inflame the liver. This process is associated with sepsis-related liver failure and greater reliance on vasopressor support. Protective microbial metabolites, such as indole-3-propionic acid (IPA), decrease significantly during sepsis, removing key anti-inflammatory signals and potentially prolonging recovery. Clinically, SALI most commonly presents as septic cholestasis with elevated bilirubin and mild transaminase changes, although conventional liver function tests are insufficiently sensitive for early detection. Novel biomarkers, including protein panels and non-coding RNAs, as well as dynamic liver function tests such as LiMAx (currently in phase II diagnostics) and ICG-PDR, offer promise for improved diagnosis and prognostication. Specifying the developmental stage of these biomarkers, such as identifying LiMAx as phase II, informs investment priorities and translational readiness. Current management is primarily supportive, emphasizing infection control and organ support. Investigational therapies include immunomodulation tailored to immune phenotypes, metabolic and mitochondrial-targeted agents such as pemafibrate and dichloroacetate, and interventions to restore gut microbiota balance, including probiotics and fecal microbiota transplantation. However, translational challenges remain due to limitations of animal models and patient heterogeneity. Conclusion: Future research should focus on developing representative models, validating biomarkers, and conducting clinical trials to enable personalized therapies that modulate inflammation, restore metabolism, and repair the gut-liver axis, with the goal of improving outcomes in SALI. Full article

Enterovirus A71 (EV-A71) is a critical global pathogen, primarily causing Hand-Foot-and-Mouth Disease (HFMD) but frequently leading to severe neurological complications, including fatal neurogenic pulmonary edema (PE). This review elucidates the complex interplay between viral pathogenesis and the host immune response. EV-A71 utilizes receptors like SCARB2 and PSGL-1 for entry, while its proteases (2A^pro, 3C^pro) efficiently evade innate immunity by cleaving key signaling adaptors (MAVS, TRIF), suppressing Type I IFN response. Critical to disease progression is the age-dependent vulnerability in infants and the subsequent shift toward immunopathology. Severe disease is driven by a systemic cytokine storm and T cell dysregulation, characterized by a loss of control from Treg cells and a profound Th17/Treg imbalance, resulting in high levels of pathogenic cytokines (e.g., IL-17A, IFN-γ). Clinical progression is predicted by specific biomarkers, including Treg depletion, monocyte exhaustion (PD-1/PD-L1), and suppressed regulatory signaling (low cAMP). These findings highlight that effective therapeutic strategies must target host-mediated damage through immunomodulation (e.g., by exploring interventions against key pathogenic axes like IL-6 and IL-1β) and call for the development of next-generation vaccines capable of eliciting balanced cellular immunity to prevent immunopathology. Full article

Background and Objectives: Despite major advances in medical science and critical care, sepsis remains a leading cause of morbidity and mortality worldwide: it arises from dysregulated host response to infections and may culminate in organ dysfunction. A hallmark of its pathogenesis is the cytokine storm, in which interleukins (ILs) serve as central mediators of both protective and deleterious immune responses. This review summarizes the current knowledge on the role of ILs in sepsis, emphasizing their potential as biomarkers and therapeutic targets. Material and Methods: We analyzed recent clinical and experimental studies focusing on the most studied ILs—including IL-1, IL-6, IL-10, IL-8, IL-12, IL-18, and IL-17—in the pathophysiology of sepsis. Attention was given to mechanistic insights, prognostic significance, and therapeutic strategies targeting IL pathways. Results: IL-1 and IL-6 emerged as key pro-inflammatory mediators, amplifying vascular permeability, coagulation activation, and shock, with IL-6 validated as a robust prognostic biomarker. IL-10 was identified as a pivotal anti-inflammatory cytokine, limiting tissue injury but fostering immunosuppression and secondary infections. Other ILs, such as IL-8, IL-12, IL-18, and IL-17, contributed to neutrophil recruitment, Th1/Th17 activation, organ-specific injury, and sepsis susceptibility. Therapeutic interventions targeting ILs, including the IL-1 receptor antagonist anakinra and IL-6 receptor blockade with tocilizumab, have shown promise in selected patient subgroups. Conclusions: ILs are central to the immunopathology of sepsis, acting both as drivers of hyperinflammation and mediators of immunosuppression. Their dual role underscores the relevance of ILs as diagnostic and prognostic biomarkers, as well as context-dependent therapeutic targets. Future approaches should prioritize precision immunomodulation aligned with the principles of personalized medicine to improve clinical outcomes in sepsis. Full article

The H6N6 avian influenza virus has expanded its host range from birds to mammals. Some strains can now bind to human-like receptors, raising concerns about human infection. Although H6N6 is a low-pathogenic avian influenza virus (LPAIV), it is unclear whether it triggers pyroptosis in human lungs, a process linked to cytokine storms in infections like H7N9. Here, we found that the chicken-origin H6N6 LPAIV can effectively replicate in and infect human alveolar macrophages and their M1 macrophages. Viral infection of M1 macrophages upregulated the mRNA levels of NLRP3, caspase-1, and Gasdermin D (GSDMD). Subsequently, caspase-1 was activated and cleaved GSDMD protein into its N-terminal fragment (GSDMD-N), which formed pores in the cell membrane and triggered the release of IL-1β and IL-18. Further analysis demonstrated that inhibition of the NLRP3/Caspase-1/GSDMD pathway by specific inhibitors attenuated pyroptosis in infected M1 macrophages. In summary, our study revealed that H6N6 virus infection induces M1 macrophage pyroptosis via the NLRP3/caspase-1/GSDMD pathway. Notably, M1 macrophages inherently produce pro-inflammatory cytokines; their pyroptosis, accompanied by the release of IL-1β and IL-18, can amplify inflammation and potentially trigger a cytokine storm in the lungs. These findings reveal novel pathogenic mechanisms and potential therapeutic targets for avian influenza viruses. Full article

Dengue virus serotype 2 (DENV-2) is a predominant cause of severe dengue and a key determinant of dengue-associated liver injury. This review integrates recent findings on the molecular and cellular mechanisms of DENV-2 hepatotropism, focusing on viral replication, cellular stress responses, and immune-mediated damage. The interplay between hepatocytes, Kupffer cells, and innate and adaptive immune responses, culminating in cytokine storm and immune-mediated hepatocyte apoptosis, is dissected. Integrating in vitro and in vivo findings, this review highlights how viral replication and immune dysregulation converge to cause hepatic injury. Future research should prioritize antiviral, immunomodulatory, and hepatoprotective approaches aimed at reducing the risk of dengue-associated liver failure. Full article

Artificial intelligence (AI) is increasingly transforming biomedical research and patient care by integrating complex biological, radiological, and healthcare information. In the field of viral respiratory infections, AI-driven approaches have shown great promise in elucidating the complexity of lung immune responses and the dynamic interplay between host and pathogen. Applications include predicting cytokine storm and acute respiratory distress syndrome (ARDS), integrating imaging findings with immunological and laboratory data, and identifying molecular and cellular signatures through single-cell and multi-omics analyses. Similar methodologies have been applied to influenza and respiratory syncytial virus (RSV), providing insights into the mechanisms distinguishing protective from maladaptive pulmonary immunity. This narrative review summarizes current evidence on how AI can evolve into a form of translational intelligence, capable of bridging mechanistic immunology with clinical application. The review explores AI-based models for disease severity prediction, patient stratification, and therapeutic response assessment, as well as emerging approaches in drug repurposing and vaccine response prediction. By integrating biological complexity with clinical context, AI offers new opportunities to uncover immune signatures predictive of antiviral or immunomodulatory efficacy and to guide personalized management strategies. Full article

Sepsis-associated acute kidney injury (SA-AKI) is a prevalent and life-threatening complication in critically ill children, contributing to high mortality rates (up to 30%) and long-term renal dysfunction in pediatric intensive care units. This review synthesizes recent advances in the signalling pathways underlying SA-AKI, emphasizing pediatric-specific mechanisms, biomarkers, and therapeutic targets. This review covers inflammatory cascades via TLR/NF-κB leading to cytokine storms (IL-6, TNF-α); apoptosis and necrosis involving mitochondrial Bcl-2 dysregulation and OLFM4; and emerging processes like pyroptosis (NF-κB-mediated), metabolic reprogramming (choline deficiency and Nrf2-mitophagy), and novel routes such as cGAS-STING and TGF-β signalling. Biomarkers like urinary OLFM4, DKK3, NGAL, and serum suPAR, alanine, and Penkid enable early diagnosis and risk stratification, with models like PERSEVERE-II enhancing prognostic accuracy. Therapeutic strategies include fluid optimization, renal replacement therapies (CRRT, SLED-f), and pathway-targeted interventions such as choline supplementation, oXiris for cytokine removal, Humanin for immunomodulation, and investigational cGAS-STING inhibitors. Despite progress, challenges persist in translating animal models to pediatric trials and addressing heterogeneity. Integrating multi-omics and precision medicine holds promise for improving outcomes, underscoring the need for multicenter studies in children. Full article