Sepsis is a life-threatening syndrome characterized by dysregulated host responses to infection, often progressing to multiple organ dysfunction syndrome (MODS). Recent evidence highlights macrophage metabolic reprogramming as a critical driver of immune responses, yet macrophages operate within a broader immunometabolic network involving dendritic cells, neutrophils, and lymphocytes that collectively shape sepsis outcomes. The coordination of these metabolic changes across multicellular interactions and their contribution to organ-specific vulnerability remain poorly understood. Here we present a holistic framework linking macrophage metabolism to multicellular communication and organ vulnerability. We discuss how glycolysis, amino acid metabolism, and fatty acid oxidation alter macrophage states via epigenetic and signaling mechanisms, producing metabolites that connect metabolism to inflammation. These signals reshape cellular networks through cytokines, extracellular vesicles, and damage-associated molecule patterns (DAMPs), differentially impacting organs with diverse metabolic demands, including the heart, lung, liver, kidney, brain, and intestine, resulting in distinct injury patterns. Our framework enhances understanding of sepsis-induced organ heterogeneity and advocates for stage-specific, organ-targeted therapies that consider integrated multicellular immunometabolic contributions.

BACKGROUND:Coronavirus disease 2019 (COVID-19) is characterized by dysregulated immune responses and excessive inflammation, contributing to severe disease and mortality. Interleukin-1 receptor type 2 (IL1R2), a decoy receptor for interleukin-1 (IL-1), regulates inflammatory responses; however, its cellular distribution and clinical significance in COVID-19 remain unclear. METHODS:Publicly available single-cell RNA sequencing (scRNA-seq) dataset (GSE149689) of peripheral blood mononuclear cells (PBMCs) from COVID-19 patients were analyzed. An independent monocyte transcriptomic dataset (GSE198256) was analyzed to evaluate IL1R2 dynamics during COVID-19 and recovery. Differential expression, functional enrichment, regulon activity, and CellChat analyses were performed to characterize IL1R2⁺ monocytes. Serum IL1R2 levels were measured in COVID-19 patients and healthy controls (HCs), and their associations with disease severity and mortality were evaluated. RESULTS:Single-cell analysis revealed that IL1R2 was predominantly expressed in monocytes from COVID-19 patients. IL1R2 expression was increased during active COVID-19 and decreased after recovery. IL1R2⁺ monocytes exhibited enhanced inflammatory transcriptional programs, increased activity of inflammation-associated regulons, and activation of TNFα/NF-κB, interferon, and IL6-JAK-STAT3 pathways. Cell-cell communication analysis identified IL1R2⁺ monocytes as active mediators of CCL, CXCL, IL1, and TNF signaling networks. Serum IL1R2 levels were elevated in COVID-19 patients, further increased in non-survivors, and correlated with inflammatory markers, tissue injury indicators, and coagulation abnormalities. IL1R2 showed predictive performance for mortality comparable to procalcitonin and D-dimer. CONCLUSIONS:IL1R2 identifies a highly inflammatory monocyte state associated with COVID-19 immune dysregulation. Elevated IL1R2 levels reflect disease activity and poor outcomes, supporting its potential role as a complementary prognostic biomarker and therapeutic target.

Background/Objectives: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by B-cell hyperactivation and excessive autoantibody production. Z-DNA binding protein 1 (ZBP1), an innate immune sensor involved in nucleic acid recognition and cell death signaling, has been implicated in antiviral and inflammatory responses. However, its role in B-cell dysregulation during SLE remains unclear. Methods: Integrative transcriptomic analyses were performed using public datasets (GSE61635, GSE235658, GSE136035, and GSE163497) to determine the expression pattern and biological functions of ZBP1 in SLE. Bulk RNA-seq and single-cell RNA-seq data were used to evaluate ZBP1 expression across B-cell subsets. Correlations between ZBP1 expression, disease activity, and immunological parameters were assessed. RNA-seq data following ZBP1 knockdown were analyzed to explore its potential downstream pathways and molecular networks. In addition, in vitro ZBP1 knockdown experiments were conducted to examine its effects on B-cell activation, plasma cell differentiation, and antibody production. Results: ZBP1 was significantly upregulated in peripheral blood and B cells from SLE patients and was enriched in pathways related to type I interferon signaling and cytokine-mediated immune responses. Single-cell transcriptomic profiling further revealed elevated ZBP1 expression across multiple B-cell subsets, including naïve B cells, memory B cells, age-associated B cells (ABCs), and plasma cells. Clinically, ZBP1 expression in peripheral B cells was positively correlated with CD86 mean fluorescence intensity (MFI), SLE Disease Activity Index (SLEDAI) scores, and serum IgG levels, suggesting a link between ZBP1 and B-cell activation. RNA-seq analysis following ZBP1 silencing demonstrated that ZBP1 regulates genes involved in the cell cycle, DNA replication, and p53 signaling, indicating its potential role in promoting B-cell proliferation and activation. Functionally, ZBP1 silencing impaired B-cell activation, reduced plasma cell differentiation, and decreased immunoglobulin production in vitro. Conclusions: Our study identifies ZBP1 as a molecule upregulated in SLE B cells and associated with B-cell activation and disease activity. Although direct causality remains to be established, the data indicate that ZBP1 may contribute to SLE pathogenesis by modulating cell cycle-related pathways and promoting aberrant B-cell responses, highlighting its potential as a biomarker and a candidate therapeutic target in SLE.

OBJECTIVE:To investigate natural killer (NK) cell dysfunction in anti-MDA5 autoantibody-positive (anti-MDA5⁺) clinically amyopathic dermatomyositis (CADM) patients with rapidly progressive interstitial lung disease (RP-ILD), and explore potential mechanisms related to macrophage activation. METHODS:Differentially expressed genes (DEGs) in peripheral blood mononuclear cells (PBMCs) from anti-MDA5+ CADM and anti-Jo1-positive (anti-Jo-1+) dermatomyositis patients were profiled using the Illumina HT-12 v4 chip. Cytokine profiles were analyzed using ELISA, and flow cytometry was performed to assess PBMC subsets, NK cell cytotoxicity, and the activation of PLC-γ2 and MAPK signaling. IgG purified from patient serum was used to assess antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP) in THP-1/THP-1-like macrophages under poly(I:C) stimulation. RESULTS:Anti-MDA5⁺ CADM patients exhibited downregulated expression of NK cell activation receptor genes and elevated cytokines such as sCD163 and ferritin compared to anti-Jo-1⁺ patients. NK cell percentages in PBMCs were prominently decreased in anti-MDA5+ patients with RP-ILD compared to those without, and NK cell cytotoxicity or degranulation was weakened, as shown by decreased CD107a and perforin expression, while monocyte populations were increased in RP-ILD patients. IgG purified from anti-MDA5⁺ patient serum impaired NK-cell degranulation in vitro and enhanced ADCC/ADCP activity of THP-1 macrophages following poly(I:C) stimulation. These effects were reduced by CD16 knockdown, indicating involvement of FcγRIII (CD16) dependent interactions. PBMCs from RP-ILD patients exhibited hypophosphorylation of PLCγ2 and ERK, along with hyperphosphorylation of p38, consistent with altered downstream signaling associated with CD16 engagement. CONCLUSION:NK-cell dysfunction and enhanced macrophage activation in anti-MDA5⁺ CADM patients with RP-ILD are associated with dysregulated CD16-dependent IgG-cell interactions and perturbations in downstream PLCγ2-MAPK signaling. These findings highlight FcγR-mediated immune dysregulation as a potential contributor to the severe inflammatory phenotype characteristic of RP-ILD, while not establishing antigen-specific mechanisms.

Sepsis, a life-threatening organ dysfunction caused by a dysregulated host response to infection, remains a critical global health challenge with mortality rates exceeding 20 % in affected populations. The liver, a frontline immune organ, plays a dual role in sepsis-acting as both a guardian against systemic infections and a vulnerable target for injury. Metabolic dysfunction-associated steatotic liver disease (MASLD), affecting nearly 30 % of the global population, significantly amplifies sepsis susceptibility, with MASLD patients exhibiting doubled infection-related mortality rates compared to healthy controls. Central to this nexus are liver sinusoidal endothelial cells (LSECs), specialized gatekeepers of hepatic immune surveillance and metabolic homeostasis. In MASLD, LSECs undergo significant structural and functional changes, triggered by lipotoxicity, oxidative stress, and chronic inflammation. These structural and functional derangements impair pathogen clearance, disrupt immune regulation, and promote systemic leakage of gut-derived toxins. LSECs further orchestrate pathogenic crosstalk with hepatocytes, Kupffer cells (KCs) and hepatic stellate cells (HSCs), fueling hepatic immune dysregulation and increasing sepsis risk. This review synthesizes evidence positioning LSECs as pivotal mediators bridging MASLD progression to sepsis vulnerability, highlighting therapeutic strategies targeting LSECs dysfunction to mitigate infection risks in metabolic liver disease.

OBJECTIVES:Idiopathic inflammatory myopathies (IIM) are autoimmune disorders with distinct subtype features, but their molecular mechanisms remain unclear. This study integrated multiomics data to identify subtype-specific molecular signatures and evaluate their prognostic significance in a Han Chinese IIM cohort. METHODS:RNA sequencing, proteomics, and metabolomics were generated on muscle tissues from 203 patients with IIM (including 44 in a validation cohort) and 18 controls. Differential expression was analysed for exons, intron retentions (IRs), proteins, and metabolites, integrated via multiomics factor analysis (MOFA). Pathway enrichment, single-sample Gene Set Enrichment Analysis (ssGSEA), correlation with clinical features, receiver operating characteristic curve, and survival analyses were conducted. RESULTS:MOFA distinguished dermatomyositis (DM), immune-mediated necrotising myopathy (IMNM), and antisynthetase syndrome (ASyS) from controls, identifying 798, 748, and 297 subtype-specific features and pathways, respectively, which were further validated in an independent cohort. In DM, upregulated interferon (IFN) and cytokine pathways were prominent, with 11 IFN-related genes altered at exon, IR, and protein levels, alongside changes in related metabolites. IFNs and cytokine scores correlated with skin manifestations, perifascicular atrophy/necrosis, inflammation, and relapse risk. IMNM showed changes in myosin, actin, and troponin genes, with enrichment of cytoskeleton and extracellular matrix (ECM) pathways that were positively linked to muscle necrosis, regeneration, and inflammation. Protein-level of ECM-related pathways predicted a favourable prognosis. ASyS displayed distinct metabolic signatures (nucleosides, ketones, phosphatidylserine) and endothelial dysfunction, with key metabolism-regulated genes (FABP3, AKR1C2, AKR1C3) showing multiomics alterations associated with necrosis, inflammation, and prognosis. CONCLUSIONS:This multiomics analysis elucidates distinct molecular mechanisms in IIM subtypes, identifying potential biomarkers for personalised prognosis and therapy.

METTL3, an m6A methyltransferase, enhances germinal center responses. This study explores its role in lupus B cells and its impact on B-cell activation. METTL3 and m6A levels in B cells from systemic lupus erythematosus (SLE) patients and lupus-prone mice were analyzed using m6A dot blot, RT-qPCR, western blotting, and flow cytometry. B-cell activation and differentiation were induced with lipopolysaccharide (LPS). The effects of METTL3 overexpression or inhibition on B-cell maturation were assessed in vivo. In Raji B cells, METTL3 and PAX5 knockdowns were performed to examine their regulatory relationship. EMSA and dual-luciferase assays confirmed PAX5 binding to the METTL3 promoter, while RIP and actinomycin D assays evaluated METTL3’s interaction with PAX5 mRNA. MeRIP-seq profiled m6A modifications across B-cell subsets. METTL3 expression and m6A levels were significantly elevated in B cells from SLE patients, with METTL3 levels positively correlating with disease activity. Elevated m6A and METTL3 levels were observed in both naïve and activated B cells but decreased markedly during differentiation into ASCs, both in vivo and in vitro. MeRIP-seq analysis identified distinct m6A methylation patterns among B-cell subsets, particularly in key transcription factors critical for B-cell activation and differentiation. METTL3 facilitated pre-B cell development in bone marrow and maintained the balance of splenic B-cell subsets in mice. Furthermore, METTL3 preserved B-cell identity and enhanced activation. Mechanistically, METTL3 bound to PAX5 mRNA, stabilizing it via m6A modification and promoting PAX5 expression. In turn, PAX5 directly bound to the METTL3 promoter, driving its expression. The elevated expression of METTL3 in lupus B cells is linked to the maintenance of autoreactive B-cell hyperresponsiveness, contributing to the pathogenesis of SLE. The reciprocal regulation between METTL3 and PAX5 highlights a critical mechanism underlying B-cell activation and persistence in autoimmune conditions like lupus.

Myocardial ischemia/reperfusion (I/R) injury is a major cause of various adverse cardiovascular outcomes associated with excessive mitophagy and cardiomyocyte ferroptosis. Paired-related homeobox 1 (PRRX1) is a transcriptional factor involved in cardiovascular injury. However, whether and how PRRX1 regulates excessive mitophagy and cardiomyocyte ferroptosis during myocardial I/R injury remains unclear. Oxygen-glucose deprivation and reperfusion (OGD/R)-treated AC16 cardiomyocytes and myocardial I/R-induced rats were used as in vitro and in vivo models. Our results showed that PRRX1 expression was upregulated in AC16 cells after OGD/R treatment. PRRX1 silencing mitigated OGD/R-induced excessive mitophagy by increasing the mitochondrial membrane potential, adenosine triphosphate and p62 levels, and reducing LC3 II/I level in AC16 cells. In addition, PRRX1 knockdown attenuated OGD/R-induced lactate dehydrogenase (LDH) release and cardiomyocyte ferroptosis by decreasing reactive oxygen species, Fe2+ and acyl-CoA synthetase long-chain family member 4 (ACSL4) levels, and increasing glutathione (GSH) and glutathione peroxidase 4 (GPX4) levels. Furthermore, PRRX1 transcriptionally promoted FK506 binding protein 5 (FKBP5), and increased p38 MAPK activation in AC16 cells. FKBP5 overexpression reversed the effects of PRRX1 silencing on excessive mitophagy and cardiomyocyte ferroptosis in OGD/R-treated AC16 cells. These effects were mitigated by a p38 MAPK inhibitor. Finally, PRRX1 downregulation mitigated myocardial I/R injury by reducing heart infarction and creatine kinase-myocardial band (CK-MB) levels in rat models. These findings demonstrate that PRRX1 silencing attenuates OGD/R-induced excessive mitophagy and cardiomyocyte ferroptosis by decreasing FKBP5 expression and inactivating p38 MAPK signaling, indicating the cardioprotective potential of PRRX1 silencing in myocardial I/R injury.

BACKGROUND:Acute pancreatitis (AP) is a severe inflammatory disorder characterized by pancreatic self-digestion, often progressing to systemic inflammation. Despite advances in understanding its pathogenesis, effective therapeutic strategies remain limited. Heat shock factor 1 (HSF1), a critical transcription factor that maintains cellular homeostasis and regulates the stress response, is downregulated in the pancreas of L-arginine-induced AP mice. However, its role and regulatory mechanisms in the pathogenesis of AP remain unclear. This study aims to elucidate the molecular function and mechanisms of HSF1 in AP, focusing on its regulation by E1A binding protein p300 (EP300) and the downstream effects on mitophagy and inflammation. METHODS:Two distinct mouse models of AP were established using L-arginine and cerulein. Pancreatic acinar cells (AR42J) were used to study the effects of HSF1 and parkin RBR E3 ubiquitin protein ligase (PRKN) on mitophagy and inflammation. The expression and regulation between HSF1, PRKN, and EP300 were assessed using genetic and pharmacological approaches. RESULTS:HSF1 deficiency exacerbates AP severity in two distinct mouse models, with increased mortality, pancreatic necrosis, and systemic inflammation. Mechanistically, HSF1 directly binds to the promoter of PRKN, enhancing its transcriptional activity. Thus, HSF1 alleviates the inflammatory response in pancreatic acinar cells during AP by promoting PRKN-mediated mitophagy, reducing ROS production, and inhibiting NLRP3 inflammasome activation. HSF1 expression is downregulated in pancreatic acinar cells due to decreased acetylation by EP300, leading to proteasomal degradation and impaired mitophagy. Pharmacological activation of EP300 (e.g., CTB) restores HSF1 expression, enhances mitophagy, and attenuates inflammation in both in vivo and in vitro settings. CONCLUSION:These findings highlight the critical role of EP300 in regulating HSF1 acetylation and stability, which in turn modulates mitophagy and pyroptosis in AP. Targeting EP300 and its downstream pathways, such as HSF1-PRKN axis, may offer novel therapeutic strategies for AP.

The journal retracts the article, “Mipu1 protects H9c2 myogenic cells from hydrogen peroxide-induced apoptosis through inhibition of the expression of the death receptor Fas” [...]

Introduction: Infection and coagulation dysfunction are two major features of sepsis, and TFPI2 exhibits both antimicrobial and anticoagulant properties. This study aims to evaluate whether TFPI2 is associated with the severity of sepsis, thereby determining its potential value in sepsis diagnosis and prognosis. Methods: Serum TFPI2 concentrations were measured and compared among 32 healthy controls, 16 intensive care unit (ICU) nonsepsis patients, and 106 ICU sepsis patients. Correlation analysis was performed between various indicators and TFPI2 levels in sepsis patients. Logistic regression analysis and receiver operating characteristic curves were used to assess the value of TFPI2 in predicting 28-day mortality in sepsis. Results: Sepsis patients exhibited markedly elevated serum TFPI2 levels compared with both healthy individuals and ICU patients without sepsis. Serum TFPI2 levels were significantly correlated with sepsis severity indicators such as Sequential Organ Failure Assessment score, Acute Physiology and Chronic Health Evaluation II score, Lac, coagulation markers including International Society on Thrombosis and Hemostasis overt disseminated intravascular coagulation criteria and Sepsis-Induced Coagulopathy scores, and platelet count. Univariate and multivariate logistic regression analyses revealed that TFPI2 is an independent risk factor for 28-day mortality in sepsis. The receiver operating characteristic curve showed that TFPI2 has a significant predictive value for 28-day mortality in sepsis, with an area under the curve of 0.832 and an optimal cutoff value of 8.316. Conclusions: This study indicates that serum TFPI2 levels hold promise as a biomarker for predicting the severity of sepsis.

BACKGROUND:Lupus nephritis (LN) can severely compromise kidney function, with podocyte injury recognized as a key pathogenic event. This study aimed to elucidate the role of circular RNA circLRCH3 in LN and to clarify its underlying molecular mechanisms. METHODS:The expression of circLRCH3 was evaluated in renal tissues and serum samples from LN patients, as well as in human podocyte cells (HPCs) treated with LN-derived immunoglobulin G (LN-IgG). The functional significance of circLRCH3 was examined in vitro and in vivo through its knockdown in LN-IgG-induced HPCs and MRL/lpr lupus-prone mice, respectively. Interactions among circLRCH3, fused in sarcoma (FUS), and interferon-induced protein 35 (IFI35) were explored using RNA immunoprecipitation and RNA pulldown assays. Podocyte pyroptosis and autophagy were analyzed by Western blotting and immunofluorescence. RESULTS:circLRCH3 was significantly upregulated in both LN patient samples and LN-IgG-induced HPCs. Silencing circLRCH3 in MRL/lpr mice attenuated renal pathological damage and improved renal function. In HPCs, circLRCH3 knockdown suppressed pyroptosis, enhanced autophagy, and increased cell viability. Mechanistically, circLRCH3 was found to bind to FUS, thereby stabilizing IFI35 mRNA. This interaction inhibited autophagy and exacerbated pyroptosis in podocytes. CONCLUSION:circLRCH3 is upregulated in LN and contributes to podocyte injury by inhibiting autophagy and promoting pyroptosis through the FUS-IFI35 pathway. Thus, targeting circLRCH3 may offer a novel therapeutic approach for LN.

INTRODUCTION:Talaromyces marneffei is a pathogenic dimorphic fungus known for causing severe opportunistic infections that can be life-threatening. The fungus is most commonly found in Southeast Asia and southern China. CASE REPORT:This case report describes the case of a young male patient infected with T. marneffei who was neither human immunodeficiency virus (HIV)-positive nor possessed anti-IFN-γ antibodies, and who resided outside the typical endemic regions. The patient developed cough and sputum three months after the removal of the left arm fracture fixator, and was initially misdiagnosed with tuberculosis; however, the response to anti-tuberculosis treatment was not good. The diagnosis of subsequent recurrence was unknown. The condition recurred during the illness, and he was ultimately diagnosed with talaromycosis via metagenomic next-generation sequencing (mNGS). The patient's condition improved after appropriate treatment with liposomal amphotericin B. CONCLUSIONS:Previous studies have found that T. marneffei infections are concentrated in patients with acquired immunodeficiency syndrome due to HIV infection, and in anti-IFN-γ antibody-positive patients. However, infections are increasing in individuals who are not immunosuppressed and are often misdiagnosed and underdiagnosed during the initial course of the disease. Therefore, clinicians should be aware that mNGS is an effective technique for detecting T. marneffei infection in non-endemic areas where they encounter non-HIV infected patients. This case report aims to raise the awareness of physicians regarding this rare disease in non-endemic areas and non-HIV patients.

Immune cell metabolic reprogramming toward glycolysis is vital for sepsis defense. While interleukin 1 receptor 2 (IL1R2) acts as a decoy receptor for IL1α/β, its potential impact on cell metabolism and death during sepsis remains unclear. This study observed elevated plasma soluble IL1R2 (sIL1R2) levels in septic patients and mice. In pyroptotic macrophages, reduced intracellular IL1R2 expression led to its release extracellularly. Proteomic screening identified enolase 1 (ENO1), a key glycolysis enzyme, as the binding partner of IL1R2 in macrophages. IL1R2 suppresses ENO1 activity to inhibit glycolysis, gasdermin D (GSDMD)-mediated pyroptosis, and inflammation in macrophages. IL1R2-deficient mice exhibited heightened susceptibility to sepsis, with increased inflammation, organ injury, and mortality. Notably, ENO1 inhibition reduced inflammation, organ injury, and improved survival rates in septic mice. The study reveals that IL1R2 interacts with ENO1 to inhibit glycolysis-mediated pyroptosis and inflammation in sepsis, suggesting the IL1R2-ENO1 interaction as a promising therapeutic target of sepsis.

Systemic sclerosis (SSc) is a rare and heterogeneous connective tissue disease. Lung diseases, including interstitial lung disease (ILD), pulmonary fibrosis (PF), and pulmonary artery hypertension (PAH), represent a significant and often fatal complication of SSc. The objective of the present study was to identify hub genes, and to establish a theoretical foundation for the pursuit of potential therapeutic targets. The data employed in this study were sourced from the Gene Expression Omnibus (GEO) data-base. The functional enrichment analysis revealed the presence of several enriched pathways that were commonly involved in SSc-ILD, SSc-PH, and SSc-PAH. These pathways included biological adhesion, cell migration, collagen containing extracellular matrix, and others. Subsequently, seven common DEGs and twelve hub genes were identified as being upregulated in all three datasets. Additionally, five pivotal genes (COL1A2, COL3A1, COL15A1, THY-1, and CCL19) demonstrated notable concordance between the two methods and were thus validated as being upregulated in the lung tissues of SSc-PF mice by qPCR. The biological adhesion, cell migration, and collagen biosynthesis-related pathways were found to be closely associated with SSc-ILD, SSc-PH, SSc-PAH, and COL1A2, COL3A1, COL15A1, THY-1, and CCL19. These may serve as key genes for early warning, prevention, and treatment of systemic sclero-sis-associated lung diseases.

The etiology of primary Sjogren’s syndrome (pSS) is complex and not completely clear. This study was to identify key genes in pSS based on Gene Expression Omnibus (GEO). We downloaded the GSE40568, GSE80805, GSE127952, and GSE164885 mRNA expression profiles from GEO. Differentially expressed genes (DEGs) analyses were carried out by using the online analysis tool GEO2R and R. Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to elucidate the biological processes, molecular function, cellular component, and KEGG signaling pathways for the DEGs in salivary glands (SGs) and peripheral blood mononuclear cells (PBMCs). Genes co-expressed were found in PBMCs and SGs of pSS patients. RT-qPCR was performed for validation. Finally, clinical correlation analysis and receiver operator characteristic (ROC) curve analysis were performed. A total of thirty-nine up-regulated and one down-regulated genes were identified in pSS SGs. GO and KEGG pathway revealed that these DEGs were related to response to virus, and type I interferon signaling pathway. It was verified that fourteen genes were up-regulated in the SGs of pSS by RT-qPCR. Twenty up-regulated genes were identified in pSS patients PBMCs. Two genes were up-regulated in SGs and PBMCs of pSS patients, including IFI27 and IFI44L. The mRNA level of IFI27 was positively correlated with the disease activity of pSS patients. Furthermore, ROC analyses proved IFI27 may have diagnostic value for pSS. IFI27 might serve as a potential biomarker for the early diagnosis and therapy of pSS.

ABSTRACT:Objective: Sepsis represents a leading cause of global mortality, defined by a dysregulated inflammatory response. This study aims to investigate the potential causal associations between circulating inflammatory proteins and sepsis risk using a two-sample Mendelian randomization (MR) approach. Methods: Publicly available summary statistics from genomewide association studies (GWAS) were used in this study. Genetic instruments for circulating inflammatory protein were derived from a GWAS meta-analysis of 11 cohorts encompassing 14,824 European participants. The relationship between genetically predicted protein levels and sepsis-related outcomes was evaluated using aggregated data from the UK Biobank-a multicenter prospective cohort study comprising over 500,000 European participants. Analyses were stratified by age, 28-day mortality, and ICU admission. Multiple MR methods, including inverse-variance weighted (IVW), MR-Egger, and weighted median, were applied to ensure the robustness of our findings. Results: The MR analysis identified significant causal associations between inflammatory proteins and sepsis outcomes. Genetically predicted elevated levels of β-NGF are associated with a reduced risk of sepsis (odds ratio [OR] 0.77, 95% confidence interval [CI] = 0.60-0.99; P = 0.039). Among sepsis patients aged below 75 years, the risk was reduced by 30% (OR, 0.70; 95% CI = 0.52-0.93; P = 0.013). Genetically predicted increases in TRAIL (OR, 1.11; 95% CI = 1.02-1.20; P = 0.020) and VEGF-A (OR, 1.18; 95% CI = 1.02-1.37; P = 0.031) were positively associated with sepsis incidence, while genetically predicted levels of CST5 (OR, 0.81; 95% CI = 0.69-0.94; P = 0.006) and MCP-1 (OR, 0.64; 95% CI = 0.45-0.92; P = 0.015) were inversely associated with sepsis-induced mortality. Conclusion: This study provides evidence from a Mendelian randomization framework supporting the causal role for specific circulating inflammatory proteins (e.g., β-NGF, VEGF-A, and TRAIL) in influencing sepsis risk and mortality. These findings underscore the potential for therapeutic interventions targeting these proteins to mitigate sepsis risk and improve patient outcomes, along with further investigation into the underlying mechanisms and clinical implications.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are the result of an exaggerated inflammatory response triggered by a variety of pulmonary and systemic insults. The lung tissues are comprised of a variety of cell types, including alveolar epithelial cells, pulmonary vascular endothelial cells, macrophages, neutrophils, and others. There is mounting evidence that these diverse cell populations within the lung interact to regulate lung inflammation in response to both direct and indirect stimuli. The aim of this review is to provide a summary and discussion of recent advances in the understanding of the importance of cell-cell crosstalk in the pathogenesis of ALI/ARDS, with a specific focus on the cell-cell interactions that may offer prospective therapeutic avenues for ALI/ARDS.