H-151 attenuates lipopolysaccharide-induced acute kidney injury by inhibiting the STING-TBK1 pathway.

Sepsis is a severe systemic infectious disease that often leads to multi-organ dysfunction. One of the common and serious complications of sepsis is renal injury. In this study, we aimed to investigate the potential mechanistic role of a novel compound called H-151 in septic kidney injury. We also examined its impact on renal function and mouse survival rates. Initially, we confirmed abnormal activation of the STING-TBK1 signaling pathway in the kidneys of septic mice. Subsequently, we treated the mice with H-151 and observed significant improvement in sepsis-induced renal dysfunction. This was evidenced by reductions in blood creatinine and urea nitrogen levels, as well as a marked decrease in inflammatory cytokine levels. Furthermore, H-151 substantially improved the seven-day survival rate of septic mice, indicating its therapeutic potential. Importantly, H-151 also exhibited an inhibitory effect on renal apoptosis levels, further highlighting its mechanism of protecting against septic kidney injury. These study findings not only offer new insights into the treatment of septic renal injury but also provide crucial clues for further investigations into the regulatory mechanisms of the STING-TBK1 signaling pathway and potential drug targets.

Psychosomatic mechanisms of heart failure symptoms on quality of life in patients with chronic heart failure: A multi-centre cross-sectional study.

AIMS: To determine the contributions of different kinds of symptoms to the quality of life and mediating effect of psychological and physical symptoms between heart failure symptoms and quality of life. DESIGN: A multi-centre cross-sectional study. METHODS: 2006 chronic heart failure patients from four cities were recruited in China from January 2021 to December 2022. Patients' symptoms and quality of life were self-reported, and data were analysed using correlation analysis, dominance analysis and mediating effects analysis. RESULTS: The dominance analysis revealed that the overall mean contributions of heart failure, psychological and physical symptoms were .083, .085 and .111; 29.5%, 30.2% and 39.5% of the known variance. And heart failure symptoms could negatively affect quality of life through psychological and physical symptoms, accounting for 28.39% and 22.95% of the total effect. Heart failure symptoms could also affect quality of life through the chain-mediated effect of physical and psychological symptoms, accounting for 16.74%. CONCLUSIONS: Physiological symptoms had the strongest effect on quality of life and heart failure symptoms had the weakest. Most of the effect for heart failure symptoms on quality of life in chronic heart failure patients was mediated by psychological and physiological symptoms. RELEVANCE TO CLINICAL PRACTICE: It is important to design non-pharmacological intervention plans for the enhancement of physical and psychological symptoms' management skills, to reduce the adverse impact of heart failure symptoms on quality of life. REPORTING METHOD: Study methods and results reported in adherence to the STROBE checklist. NO PATIENT OR PUBLIC CONTRIBUTION: No patients or members of the public were involved in the study.

The roles of tissue-resident macrophages in sepsis-associated organ dysfunction.

Sepsis, a syndrome caused by a dysregulated host response to infection and characterized by life-threatening organ dysfunction, particularly septic shock and sepsis-associated organ dysfunction (SAOD), is a medical emergency associated with high morbidity, high mortality, and long-term sequelae. Tissue-resident macrophages (TRMs) are a subpopulation of macrophages derived primarily from yolk sac progenitors and fetal liver during embryogenesis, located primarily in non-lymphoid tissues in adulthood, capable of local self-renewal independent of hematopoiesis, and developmentally and functionally restricted to the non-lymphoid organs in which they reside. TRMs are the first line of defense against life-threatening conditions such as sepsis, tumor growth, traumatic-associated organ injury, and surgical-associated injury. In the context of sepsis, TRMs can be considered as angels or demons involved in organ injury. Our proposal is that sepsis, septic shock, and SAOD can be attenuated by modulating TRMs in different organs. This review summarizes the pathophysiological mechanisms of TRMs in different organs or tissues involved in the development and progression of sepsis.

Factors affecting do-not-attempt-resuscitation (DNAR) decisions among adult patients in the emergency department of a general tertiary teaching hospital in China: a retrospective observational study.

OBJECTIVE: Do-not-attempt-resuscitation (DNAR) orders are designed to allow patients to opt out of receiving cardiopulmonary resuscitation in the event of a cardiac arrest. While DNAR has become a standard component of medical care, there is limited research available specifically focusing on DNAR orders in the context of emergency departments in China. This study aimed to fill that gap by examining the factors related to DNAR orders among patients in the emergency department of a general tertiary teaching hospital in China. DESIGN: Retrospective observational study. SETTING: Emergency department. PARTICIPANTS: This study and analysis on adult patients with DNAR or no DNAR data between 1 January 2022 and 1 January 2023 in the emergency department of a large academic comprehensive tertiary teaching hospital. A total of 689 were included in our study. PRIMARY OUTCOME MEASURES: Whether the patient received DNAR was our dependent variable. RESULTS: Among the total patients, 365 individuals (53.0%) had DNAR orders. The following variables, including age, sex, age-adjusted Charlson comorbidity index (ACCI), primary diagnosis of cardiogenic or cancer related, history of neurological dysfunction or cancer, were independently associated with the difference between the DNAR group and the no DNAR group. Furthermore, there were significant statistical differences observed in the choice of DNAR among patients with different stages of cancer. CONCLUSIONS: In comparison to the no DNAR group, patients with DNAR were characterised by being older, having a higher proportion of female patients, higher ACCI scores, a lower number of patients with a primary diagnosis of cardiogenic and a higher number of patients with a primary diagnosis of cancer related, history of neurological dysfunction or cancer.

Angiotensin-(1-7) ameliorates sepsis-induced cardiomyopathy by alleviating inflammatory response and mitochondrial damage through the NF-κB and MAPK pathways.

BACKGROUND: There is no available viable treatment for Sepsis-Induced Cardiomyopathy (SIC), a common sepsis complication with a higher fatality risk. The septic patients showed an abnormal activation of the renin angiotensin (Ang) aldosterone system (RAAS). However, it is not known how the Ang II and Ang-(1-7) affect SIC. METHODS: Peripheral plasma was collected from the Healthy Control (HC) and septic patients and Ang II and Ang-(1-7) protein concentrations were measured. The in vitro and in vivo models of SIC were developed using Lipopolysaccharide (LPS) to preliminarily explore the relationship between the SIC state, Ang II, and Ang-(1-7) levels, along with the protective function of exogenous Ang-(1-7) on SIC. RESULTS: Peripheral plasma Ang II and the Ang II/Ang-(1-7) levels in SIC-affected patients were elevated compared to the levels in HC and non-SIC patients, however, the HC showed higher Ang-(1-7) levels. Furthermore, peripheral plasma Ang II, Ang II/Ang-(1-7), and Ang-(1-7) levels in SIC patients were significantly correlated with the degree of myocardial injury. Additionally, exogenous Ang-(1-7) can attenuate inflammatory response, reduce oxidative stress, maintain mitochondrial dynamics homeostasis, and alleviate mitochondrial structural and functional damage by inhibiting nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways, thus alleviating SIC. CONCLUSIONS: Plasma Ang-(1-7), Ang II, and Ang II/Ang-(1-7) levels were regarded as significant SIC biomarkers. In SIC, therapeutic targeting of RAAS, for example with Ang-(1-7), may exert protective roles against myocardial damage.

RNF20 deletion causes inflammation in model of sepsis through the NLRP3 activation.

Aim: Sepsis is an extremely complex, threatening and difficult-to-treat disease, which can occur at any age and under any underlying disease. RNF20 regulate NF-kappaB (NF-κB) signaling pathway and the transcription of inflammatory factors of target genes. Therefore, it is of great significance to study the function of RNF20 in the clinical treatment of sepsis and its underlying mechanisms.Methods: C57BL/6 mice were subjected to cecal ligation and puncture (CLP) surgery. THP-1 cells were induced with Lipopolysaccharide for 4 h.Results: RNF20 gene, mRNA expression and protein expression were reduced in patients with sepsis and mice with sepsis. Based on RNF20 deletion (RNF20-/-) mice, these were found to be increased inflammation reactions in RNF20-/- mice. However, the RNF20 human protein reduced inflammation reactions in mice with sepsis. In vitro model of sepsis, over-expression of RNF20 inhibited inflammation reactions by inducing Vitamin D Receptor (VDR), while down-regulation of RNF20 promoted inflammation reactions through the suppression of VDR. RNF20 protein was interlinked with VDR protein, and VDR protein was also interlinked with NLRP3. Furthermore, VDR promoted NLRP3 ubiquitination and reduced NLRP3 function in vitro model of sepsis.Conclusion: These studies demonstrate that RNF20 suppressed inflammation reactions in models with sepsis through NLRP3 inflammasome and NLRP3 ubiquitination by activating VDR.

Omega-3 polyunsaturated fatty acids inhibit cardiomyocyte apoptosis and attenuate sepsis-induced cardiomyopathy.

OBJECTIVES: Sepsis can cause myocardial injury, which is one of the leading causes of death in critically ill patients. Fish oil rich in omega-3 polyunsaturated fatty acids (PUFAs) in ultralong chains has immunomodulatory effects and can inhibit the production of various critically ill proinflammatory cytokines. Therefore, this study focused on whether ω-3 PUFAs have a protective effect on sepsis-induced cardiomyopathy (SIC). METHODS: Male 6-8 weeks old C57BL/6 mice were pretreated with 3% special fish oil supplement rat food for seven consecutive days prior to surgery. Cecal ligation and puncture (CLP) was perfromed to induce polymicrobial sepsis.The cardiac function was assessed by echocardiography, apoptosis of cardiomyocyte were detected by TUNEL assay and Western blotting, and the level of TNF-α, IL-6, and IL-1ß in plasma was determined 24h after CLP. RESULTS: Pretreatment with omega-3 PUFAs attenuated cardiomyocyte apoptosis, decreased the production of proinflammatory cytokines, attenuated the SIC, and improved the survival rate of septic mice induced by CLP. CONCLUSIONS: ω-3 PUFAs alleviate SIC through attenuating cardiomyocyte apoptosis, which provides a new direction for the prevention and treatment of SIC.

Losartan attenuates sepsis-induced cardiomyopathy by regulating macrophage polarization via TLR4-mediated NF-κB and MAPK signaling.

Sepsis-induced cardiomyopathy (SIC) is a serious complication of sepsis with high mortality but no effective treatment. The renin angiotensin (Ang) aldosterone system (RAAS) is activated in patients with sepsis but it is unclear how the Ang II/Ang II type 1 receptor (AT1R) axis contributes to SIC. This study examined the link between the Ang II/AT1R axis and SIC as well as the protective effect of AT1R blockers (ARBs). The Ang II level in peripheral plasma and AT1R expression on monocytes were significantly higher in patients with SIC compared with those in non-SIC patients and healthy controls and were correlated with the degree of myocardial injury. The ARB losartan reduced the infiltration of neutrophils, monocytes, and macrophages into the heart and spleen of SIC mice. Additionally, losartan regulated macrophage polarization from the M1 to the M2 subtype via nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways, thereby maintaining the mitochondrial dynamics balance in cardiomyocytes and reducing oxidative stress and cardiomyocyte apoptosis. In conclusion, the plasma Ang II level and AT1R expression on plasma monocytes are an important biomarker in SIC. Therapeutic targeting of AT1R, for example with losartan, can potentially protect against myocardial injury in SIC.

Diagnostic Value of Metagenomic Next-Generation Sequencing for Pulmonary Infection in Intensive Care Unit and Non-Intensive Care Unit Patients.

Objective: To evaluate the diagnostic performance of metagenomic next-generation sequencing (mNGS) and culture in pathogen detection among intensive care unit (ICU) and non-ICU patients with suspected pulmonary infection. Methods: In this prospective study, sputum samples were collected from patients with suspected pulmonary infection for 2 consecutive days and then subjected to DNA or RNA sequencing by mNGS or culture; 62 ICU patients and 60 non-ICU patients were admitted. In the end, comparisons were made on the pathogen species identified by mNGS and culture, the overall performance of these two methods in pathogen detection, and the most common pathogens detected by mNGS between the ICU and non-ICU groups. Results: In DNA and RNA sequencing, the positive rate of pathogen detection reached 96.69% (117/121) and 96.43% (108/112), respectively. In culture tests, the positive rate of the pathogen was 39.34% (48/122), much lower than that of DNA and RNA sequencing. In general, the positive rate of pathogen detection by sputum mNGS was significantly higher than that of sputum culture in the total and non-ICU groups (p < 0.001) but did not show a significant difference when compared to the result of sputum culture in the ICU group (p = 0.08). Haemophilus spp., Candida albicans, Enterococcus spp., and viruses from the mNGS results were excluded before comparing the overall performance of these two methods in pathogen detection. Specifically, among the 10 most common bacteria implied from the mNGS results, significant differences were observed in the number of cases of Haemophilus parainfluenzae, Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Staphylococcus aureus, and Enterococcus faecalis between the ICU and non-ICU groups (p < 0.05). Conclusions: This study demonstrated the superiority of mNGS over culture in detecting all kinds of pathogen species in sputum samples. These results indicate that mNGS may serve as a valuable tool to identify pathogens, especially for ICU patients who are more susceptible to mixed infections.

S100A9 and SOCS3 as diagnostic biomarkers of acute myocardial infarction and their association with immune infiltration.

Acute myocardial infarction (AMI) is one of the leading causes of death globally, with a mortality rate of over 20%. However, the diagnostic biomarkers frequently used in current clinical practice have limitations in both sensitivity and specificity, likely resulting in delayed diagnosis. This study aimed to identify potential diagnostic biomarkers for AMI and explored the possible mechanisms involved. Datasets were retrieved from the Gene Expression Omnibus. First, we identified differentially expressed genes (DEGs) and preserved modules, from which we identified candidate genes by LASSO (least absolute shrinkage and selection operator) regression and the SVM-RFE (support vector machine-recursive feature elimination) algorithm. Subsequently, we used ROC (receiver operating characteristic) analysis to evaluate the diagnostic accuracy of the candidate genes. Thereafter, functional enrichment analysis and an analysis of immune infiltration were implemented. Finally, we assessed the association between biomarkers and biological processes, infiltrated cells, clinical traits, tissues and time points. We identified nine preserved modules containing 1,016 DEGs and managed to construct a diagnostic model with high accuracy (GSE48060: AUC = 0.923; GSE66360: AUC = 0.973) incorporating two genes named S100A9 and SOCS3. Functional analysis revealed the pivotal role of inflammation; immune infiltration analysis indicated that eight cell types (monocytes, epithelial cells, neutrophils, CD8+ T cells, Th2 cells, NK cells, NKT cells and platelets) were likely involved in AMI. Furthermore, we observed that S100A9 and SOCS3 were correlated with inflammation, variably infiltrated cells, clinical traits of patients, sampling tissues and sampling time points. In conclusion, we suggested S100A9 and SOCS3 as diagnostic biomarkers of AMI and discovered their association with inflammation, infiltrated immune cells and other factors.

Frequency and mortality of sepsis and septic shock in China: a systematic review and meta-analysis.

BACKGROUND: Sepsis, a life-threatening organ dysfunction induced by infection, is a major public health problem. This study aimed to evaluate the frequency and mortality of sepsis, severe sepsis, and septic shock in China. METHODS: We Searched MEDLINE, Embase, PubMed, and Cochrane Library from 1 January 1992 to 1 June 2020 for studies that reported on the frequency and mortality of sepsis, severe sepsis, and septic shock conducted in China. Random effects models were performed to estimate the pooled frequency and mortality of sepsis, severe sepsis, and septic shock. RESULTS: Our search yielded 846 results, of which 29 studies were included in this review. The pooled frequency of sepsis was estimated at 33.6% (95% CI 25.9% to 41.3%, I2 = 99.2%; p < 0.001), and the pooled mortality of sepsis, severe sepsis and septic shock were 29.0% (95% CI 25.3%-32.8%, I2 = 92.1%; p = 0), 31.1% (95% CI 25.3% to 36.9%, I2 = 85.8%; p < 0.001) and 37.3% (95% CI 28.6%-46.0%, I2 = 93.5%; p < 0.001). There was significant heterogeneity between studies. With a small number of included studies and the changing definition of sepsis, trends in sepsis frequency and mortality were not sufficient for analysis. Epidemiological data on sepsis in the emergency department (ED) are severely lacking, and more research is urgently needed in this area is urgently needed. CONCLUSIONS: Our findings indicated that the frequency and mortality of sepsis and septic shock in China were much higher than North America and Europe countries. Based on our results, an extremely high incidence and mortality of sepsis and septic shock in China's mainland requires more healthcare budget support. Epidemiological data on sepsis and septic shock in ED are severely lacking, and more research is urgently needed in this area. Trial registration This systematic review was conducted according to the statement of the preferred reporting items for systematic review (PROSPERO CRD42021243325) and the meta-analysis protocols (PRISMA-P).

Rutin Inhibits Cardiac Apoptosis and Prevents Sepsis-Induced Cardiomyopathy.

Rutin is a flavanol-type polyphenol that consists of flavanol quercetin and the disaccharide rutinose, which has been reported to exert various biological effects such as antioxidant and anti-inflammatory activities. It is not clear whether rutin has a protective effect on sepsis-induced cardiomyopathy (SIC). In this study, we used male C57BL/6 mice and cecal ligation and puncture (CLP) surgery to establish the model of SIC. Rutin was precautionarily treated (50, 100, 200 mg/kg per day, 7 days) before CLP. The results showed that rutin pretreatment (100, 200 mg/kg per day, 7 days) reduced the mortality of murine sepsis. We chose the 100 mg/kg dose for further studies. Mice were pretreatment with rutin (100 mg/kg per day, 7 days) before subjected to CLP, and myocardial tissue and blood samples were collected 24 h after CLP. Serum levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and cTNT decreased, while interleukin-10 (IL-10) increased with rutin pretreatment. The cardiomyocytes apoptosis and mitochondrial dysfunction were also alleviated with rutin pretreatment. In conclusion, this study confirmed the efficacy of rutin-enriched diet in the prophylaxis of cardiac apoptosis and cardiac injury induced by CLP in mouse model. It provides a potential new approach on SIC prophylaxis in sepsis.

Insight Into Regulatory T Cells in Sepsis-Associated Encephalopathy.

Sepsis-associated encephalopathy (SAE) is a diffuse central nervous system (CNS) dysfunction during sepsis, and is associated with increased mortality and poor outcomes in septic patients. Despite the high incidence and clinical relevance, the exact mechanisms driving SAE pathogenesis are not yet fully understood, and no specific therapeutic strategies are available. Regulatory T cells (Tregs) have a role in SAE pathogenesis, thought to be related with alleviation of sepsis-induced hyper-inflammation and immune responses, promotion of T helper (Th) 2 cells functional shift, neuroinflammation resolution, improvement of the blood-brain barrier (BBB) function, among others. Moreover, in a clinical point of view, these cells have the potential value of improving neurological and psychiatric/mental symptoms in SAE patients. This review aims to provide a general overview of SAE from its initial clinical presentation to long-term cognitive impairment and summarizes the main features of its pathogenesis. Additionally, a detailed overview on the main mechanisms by which Tregs may impact SAE pathogenesis is given. Finally, and considering that Tregs may be a novel target for immunomodulatory intervention in SAE, different therapeutic options, aiming to boost peripheral and brain infiltration of Tregs, are discussed.

Regulatory T Cells: Angels or Demons in the Pathophysiology of Sepsis?

Sepsis is a syndrome characterized by life-threatening organ dysfunction caused by the dysregulated host response to an infection. Sepsis, especially septic shock and multiple organ dysfunction is a medical emergency associated with high morbidity, high mortality, and prolonged after-effects. Over the past 20 years, regulatory T cells (Tregs) have been a key topic of focus in all stages of sepsis research. Tregs play a controversial role in sepsis based on their heterogeneous characteristics, complex organ/tissue-specific patterns in the host, the multi-dimensional heterogeneous syndrome of sepsis, the different types of pathogenic microbiology, and even different types of laboratory research models and clinical research methods. In the context of sepsis, Tregs may be considered both angels and demons. We propose that the symptoms and signs of sepsis can be attenuated by regulating Tregs. This review summarizes the controversial roles and Treg checkpoints in sepsis.

Immune checkpoints in sepsis: New hopes and challenges.

Sepsis is a life-threatening syndrome with a high incidence and a weighty economic burden. The cytokines storm in the early stage and the state of immunosuppression in the late stage contribute to the mortality of sepsis. Immune checkpoints expressed on lymphocytes and APCs, including CD28, CTLA-4, CD80, CD86, PD-1 and PD-L1, CD40 and CD40L, OX40 and OX40L, 4-1BB and 4-1BBL, BTLA, TIM family, play significant roles in the pathogenesis of sepsis through regulating the immune disorder. The specific therapies targeting immune checkpoints exhibit great potentials in the animal and preclinical studies, and further clinical trials are planning to implement. Here, we review the current literature on the roles played by immune checkpoints in the pathogenesis and treatment of sepsis. We hope to provide further insights into this novel immunomodulatory strategy.

The contribution of neuropilin-1 in the stability of CD4+ CD25+ regulatory T cells through the TGF-ß1/Smads signaling pathway in the presence of lipopolysaccharides.

INTRODUCTION: This study investigates the synergistic effect of TGF-ß1 and Nrp-1 on CD4+ CD25+ Tregs ' stabilization, and the associated pathways of signal transduction, in vitro models in the presence of LPS. MATERIALS AND METHODS: Spleen CD4+ CD25+ Tregs cells of mice models in the presence of LPS, were transfected with an shRNA targeting Nrp-1, Smad2, or Smad3, may or may not be treated with recombinant TGF-ß1. Followed by subsequent determination of cellular proliferation, rate of apoptosis, observation of the Foxp3, CTLA-4, and TGF-ß1m+ expression levels, foxp3-TSDR methylation, secretion levels of the inhibitory cytokines IL-10 and TGF-ß1, and Smad2/3 of CD4+ CD25+ Tregs expression. RESULTS: A remarkable stimulation in CD4+ CD25+ Tregs ' stability is noted after administering recombinant TGF-ß1 in the presence of LPS, and promoted cellular viability, increased Foxp3, CTLA-4, and TGF-ß1m+ expression, and elevated secretion of IL-10 and TGF-ß1. This also inhibited the apoptosis and methylation of foxp3- TSDR of CD4+ CD25+ Tregs . The shRNA transfection silenced Nrp-1 and Smad3, but not Smad2, resulting in the suppression of the recombinant TGF-ß1-mediated effects in the presence of LPS. CONCLUSIONS: According to the results, Nrp-1 mediates TGF-ß1 to improve the stability of regulatory CD4+ CD25+ T cells and maybe a possible therapeutic target with the ability to improve the CD4+ CD25+ Tregs associated negative immunoregulation that is related to the TGF-ß1/Smads cell signaling during sepsis.

The roles of macrophage polarization in the host immune response to sepsis.

Sepsis is a life-threatening clinical syndrome caused by infection. Its pathogenesis is complex and entails coagulation dysfunction, inflammation, and immune disorders. Macrophages are important components of innate and adaptive immunity that are highly heterogeneous and plastic. They can polarize into a multi-dimensional spectrum of phenotypes with different functions relating to immune regulation in response to changes in the microenvironment of specific tissues. We reviewed studies that examined the role of macrophage polarization with a focus on the classical activated (M1-like) and alternative activated (M2-like) macrophages as the two main phenotypes involved in the host immune response to sepsis. A complex regulatory network is involved in the process of macrophage polarization, which is influenced by a variety of signaling molecules, transcription factors, epigenetic modifications, and metabolic reprogramming. M1-like macrophages release large quantities of pro-inflammatory mediators, while M2-like macrophages release large quantities of anti-inflammatory mediators. An imbalance between M1-like and M2-like macrophages induces the occurrence and development of sepsis. Therefore, targeted regulation of the process of macrophage polarization could be a useful approach to normalize the immune balance of the host, offering a new treatment modality for different stages of sepsis.

Semaphorin 3A contributes to sepsis­induced immunosuppression by impairing CD4+ T cell anergy.

Semaphorin 3A (Sema3A), a member of the Sema family of proteins, appears to serve an important role in sepsis and sepsis­induced immunosuppression and has been regarded as a crucial regulator involved in cellular immune response. However, the role of Sema3A in CD4+ T cell anergy during sepsis remains to be elucidated. In the present study, the cecal ligation and perforation model and lipopolysaccharide (LPS) were used to simulate sepsis and the role of Sema3A in sepsis­induced CD4+ T cell anergy was investigated in vivo and in vitro. In vivo, the serum concentration of Sema3A was enhanced and exacerbated sepsis­induced T cell immunosuppression and multiple organ dysfunction syndromes (MODS). Administration of (­)­epigallocatechin­3­gallate, an inhibitor of Sema3A, markedly improved sepsis­induced T cell immunosuppression and MODS. In vitro, both lymphoid and myeloid lineages secreted high concentration of Sema3A in LPS­induced sepsis, especially in the lymphoid lineage. Inhibition of Sema3A alleviated T cell anergy. The NF­κB signaling pathway was involved in Sema3A­mediated autocrine loop aggravating T cell immune dysfunction during LPS­induced sepsis. Inhibiting Sema3A exerted significant improvement of sepsis­induced immunosuppression and MODS, which was associated with improvement of CD4+ T cells anergy via regulation of the NF­κB signaling pathway.