Role In Sepsis Research Articles

Activation of CD4+ T Cell-Derived Cannabinoid Receptor 2 Signaling Exacerbates Sepsis via Inhibiting IL-10.

The cannabinoid receptor 2 (CB2) is a receptor mainly expressed in immune cells and believed to be immunosuppressive in infective or inflammatory models. However, its role in sepsis has not been fully elucidated. In this study, we delineate the function and mechanism of CB2 in the cecal ligation and puncture-induced septic model in mice. The activation of CB2 signaling with HU308 led to decreased survival rates and more severe lung injury in septic mice, and lower IL-10 levels in peritoneal lavage fluid were observed in the CB2 agonist group. The mice with conditional knockout of CB2-encoding gene CNR2 in CD4+ T cells (CD4 Cre CNR2fl/fl) improved survival, enhanced IL-10 production, and ameliorated pulmonary damage in the sepsis model after CB2 activation. In addition, double-knockout of the CNR2 gene (Lyz2 Cre CD4 Cre CNR2fl/fl) decreased the susceptibility to sepsis compared with Lyz2 Cre CNR2fl/fl mice. Mechanistically, the blockade of IL-10 with the anti-IL-10 Ab abolished its protection in CD4 Cre CNR2fl/fl mice. In accordance with the animal study, in vitro results revealed that the lack of CNR2 in CD4+ cells elevated IL-10 production, and CB2 activation inhibited CD4+ T cell-derived IL-10 production. Furthermore, in the clinical environment, septic patients expressed enhanced CB2 mRNA levels compared with healthy donors in PBMCs, and their CB2 expression was inversely correlated with IL-10. These results suggested that the activation of CD4+ T cell-derived CB2 increased susceptibility to sepsis through inhibiting IL-10 production.

Unlocking the Untapped Potential of Endothelial Kinase and Phosphatase Involvement in Sepsis for Drug Treatment Design.

Sepsis is a devastating clinical condition that can lead to multiple organ failure and death. Despite advancements in our understanding of molecular mechanisms underlying sepsis and sepsis-associated multiple organ failure, no effective therapeutic treatment to directly counteract it has yet been established. The endothelium is considered to play an important role in sepsis. This review highlights a number of signal transduction pathways involved in endothelial inflammatory activation and dysregulated endothelial barrier function in response to sepsis conditions. Within these pathways – NF-κB, Rac1/RhoA GTPases, AP-1, APC/S1P, Angpt/Tie2, and VEGF/VEGFR2 – we focus on the role of kinases and phosphatases as potential druggable targets for therapeutic intervention. Animal studies and clinical trials that have been conducted for this purpose are discussed, highlighting reasons why they might not have resulted in the expected outcomes, and which lessons can be learned from this. Lastly, opportunities and challenges that sepsis and sepsis-associated multiple organ failure research are currently facing are presented, including recommendations on improved experimental design to increase the translational power of preclinical research to the clinic.

YTHDF1 alleviates sepsis by upregulating WWP1 to induce NLRP3 ubiquitination and inhibit caspase-1-dependent pyroptosis

Pyroptosis is inflammation-associated caspase-1-dependent programmed cell death, which confers a crucial role in sepsis. The present study intends to investigate the regulatory network and function of the microarray-predicted YTHDF1 in caspase-1-dependent pyroptosis of sepsis. Peripheral blood of patients with sepsis was collected to determine WWP1 and YTHDF1 expression. An in vitro sepsis cell model was induced in RAW264.7 cells using lipopolysaccharide (LPS) and ATP and an in vivo septic mouse model by cecal ligation and perforation (CLP). After gain- and loss-of-function assays in vitro and in vivo, TNF-α and IL-1β levels and the cleavage of gasdermin-D (GSDMD) were detected by ELISA and Western blot assay, followed by determination of lactate dehydrogenase (LDH) activity. Immunoprecipitation and meRIP assay were performed to detect the ubiquitination of NLRP3 and the m6A modification of WWP1 mRNA. The binding of WWP1 to YTHDF1 was explored using RIP-RT-qPCR and dual luciferase gene reporter assay. It was noted that WWP1 and YTHDF1 were downregulated in clinical sepsis samples, LPS + ATP-treated RAW264.7 cells, and CLP-induced mice. The ubiquitination of NLRP3 was promoted after overexpression of WWP1. WWP1 translation could be promoted by YTHDF1. Then, WWP1 or YTHDF1 overexpression diminished LDH activity, NLRP3 inflammasomes and caspase-1-mediated cleavage of GSDMD in LPS + ATP-induced RAW264.7 cells. Overexpressed YTHDF1 restrained inflammatory response in CLP-induced mice. Collectively, the alleviatory effect of m6A reader protein YTHDF1 may be achieved through promotion of NLRP3 ubiquitination and inhibition of caspase-1-dependent pyroptosis by upregulating WWP1.

Lysophosphatidic Acid Receptor 3 Suppress Neutrophil Extracellular Traps Production and Thrombosis During Sepsis.

Sepsis consists of life-threatening organ dysfunction resulting from a dysregulated response to infection. Recent studies have found that excessive neutrophil extracellular traps (NETs) contribute to the pathogenesis of sepsis, thereby increasing morbidity and mortality. Lysophosphatidic acid (LPA) is a small glycerophospholipid molecule that exerts multiple functions by binding to its receptors. Although LPA has been functionally identified to induce NETs, whether and how LPA receptors, especially lysophosphatidic acid receptor 3 (LPA3), play a role in the development of sepsis has never been explored. A comprehensive understanding of the impact of LPA3 on sepsis is essential for the development of medical therapy. After intraperitoneal injection of lipopolysaccharide (LPS), Lpar3 -/-mice showed a substantially higher mortality, more severe injury, and more fibrinogen content in the lungs than wild-type (WT) mice. The values of blood coagulation markers, plasma prothrombin time (PT) and fibrinogen (FIB), indicated that the Lpar3 -/- mice underwent a severe coagulation process, which resulted in increased thrombosis. The levels of NETs in Lpar3 -/- mice were higher than those in WT mice after LPS injection. The mortality rate and degree of lung damage in Lpar3 -/- mice with sepsis were significantly reduced after the destruction of NETs by DNaseI treatment. Furthermore, in vitro experiments with co-cultured monocytes and neutrophils demonstrated that monocytes from Lpar3 -/- mice promoted the formation of NETs, suggesting that LPA3 acting on monocytes inhibits the formation of NETs and plays a protective role in sepsis. Mechanistically, we found that the amount of CD14, an LPS co-receptor, expressed by monocytes in Lpar3 -/-mice was significantly elevated after LPS administration, and the MyD88-p65-NFκB signaling axis, downstream of toll-like receptor 4 signaling, in monocytes was overactivated. Finally, after an injection of the LPA3 agonist (2S)-1-oleoyl-2-methylglycero-3-phosphothionate (OMPT), the survival rate of mice with sepsis was improved, organ damage was reduced, and the production of NETs was decreased. This suggested the possible translational value and application prospects of (2S)-OMPT in the treatment of sepsis. Our study confirms an important protective role of LPA3 in curbing the development of sepsis by suppressing NETs production and thrombosis and provides new ideas for sepsis treatment strategies.

Long non-coding RNA metastasis-related lung adenocarcinoma transcript 1 (MALAT1) forms a negative feedback loop with long non-coding RNA colorectal neoplasia differentially expressed (CRNDE) in sepsis to regulate lung cell apoptosis

ABSTRACT It has been reported that long non-coding RNAs (lncRNAs) metastasis-related lung adenocarcinoma transcript 1 (MALAT1) and colorectal neoplasia differentially expressed (CRNDE) play opposite roles in sepsis. Therefore, we explored their potential interaction with sepsis. To this end, we determined MALAT1 and CRNDE levels using RT-qPCR in plasma samples collected from healthy controls (n = 60) and sepsis patients (n = 60) before and after treatment and the effects of MALAT1 and CRNDE overexpression in human bronchial epithelial cells (HBEpCs) on the expression of each other and HBEpC apoptosis. RT-qPCR analyses showed that MALAT1 was upregulated, while CRNDE was downregulated in sepsis and overexpression of MALAT1 and CRNDE downregulated the expression of each other. After proper treatment, MALAT1 was downregulated and CRNDE was upregulated in sepsis. Lipopolysaccharides (LPS) treatment of HBEpCs upregulated MALAT1 and downregulated CRNDE. Cell apoptosis analysis showed that MALAT1 overexpression promoted, while CRNDE overexpression inhibited LPS-induced HBEpC apoptosis. Moreover, CRNDE overexpression attenuated the effects of MALAT1 overexpression. Overall, MALAT1 might form a negative feedback loop with CRNDE in sepsis to regulate lung cell apoptosis.

Association Between Gut Dysbiosis and Sepsis-Induced Myocardial Dysfunction in Patients With Sepsis or Septic Shock.

ObjectiveSepsis-induced myocardial dysfunction (SIMD) seriously affects the evolution and prognosis of the sepsis patient. The gut microbiota has been confirmed to play an important role in sepsis or cardiovascular diseases, but the changes and roles of the gut microbiota in SIMD have not been reported yet. This study aims to assess the compositions of the gut microbiota in sepsis or septic patients with or without myocardial injury and to find the relationship between the gut microbiota and SIMD.MethodsThe prospective, observational, and 1:1 matched case–control study was conducted to observe gut microbiota profiles from patients with SIMD (n = 18) and matched non-SIMD (NSIMD) patients (n = 18) by 16S rRNA gene sequencing. Then the relationship between the relative abundance of microbial taxa and clinical indicators and clinical outcomes related to SIMD was analyzed. The receiver operating characteristic (ROC) curves were used to evaluate the predictive efficiencies of the varied gut microbiota to SIMD.ResultsSIMD was associated with poor outcomes in sepsis patients. The beta-diversity of the gut microbiota was significantly different between the SIMD patients and NSIMD subjects. The gut microbiota profiles in different levels significantly differed between the two groups. Additionally, the abundance of some microbes (Klebsiella variicola, Enterobacteriaceae, and Bacteroides vulgatus) was correlated with clinical indicators and clinical outcomes. Notably, ROC analysis indicated that K. variicola may be a potential biomarker of SIMD.ConclusionOur study indicates that SIMD patients may have a particular gut microbiota signature and that the gut microbiota might be a potential diagnostic marker for evaluating the risk of developing SIMD.

MicroRNA-23a-3p targeting of HMGB1 inhibits LPS-induced inflammation in murine macrophages in vitro.

Inflammatory cytokines, including high mobility group box 1 (HMGB1), play a key role in sepsis via various mechanisms, some of which remain unknown. Sepsis is a common cause of death in patients admitted to the intensive care unit. MicroRNAs (miRs) serve an important role in the inflammatory response. The present study aimed to investigate the role of miR-23a-3p in macrophage inflammation and the targeted regulation of HMGB1 expression. The murine macrophage cell line RAW264.7 was subjected to lipopolysaccharide (LPS) treatment to mimic the inflammation involved in sepsis in vitro. Reverse transcription-quantitative PCR was performed to measure miR-23a-3p expression and mRNA expression. Protein levels were determined using ELISA and western blotting. The target binding relationship between miR-23a-3p and the HMGB1 3'untranslated region was predicted and validated with a dual luciferase reporter assay. HMGB1 expression was increased and miR-23a-3p expression significantly reduced in patients with sepsis and in LPS-treated RAW264.7 cells in comparison with controls. Overexpression of miR-23a-3p reduced interleukin (IL)-6 and tumor necrosis factor (TNF)-α expression in RAW264.7 cells under LPS stimulation, while silencing of miR-23a-3p elevated the expression of IL-6 and TNF-α in comparison with controls. The inhibitory effect of miR-23a-3p on LPS-induced inflammation could be abolished by HMGB1 upregulation in RAW264.7 cells. HMGB1 was targeted by miR-23a-3p. miR-23a-3p is expressed at reduced levels during inflammation in sepsis, and overexpression of miR-23a-3p inhibits LPS-induced inflammation in murine macrophages in vitro by directly downregulating HMGB1. The results of the present study provided a novel insight into the molecular mechanism underlying HMGB1 expression at the post-transcriptional level in sepsis.

Blood long non-coding RNA intersectin 1-2 is highly expressed and links with increased Th17 cells, inflammation, multiple organ dysfunction, and mortality risk in sepsis patients.

BackgroundLong non‐coding RNA intersectin 1–2 (lnc‐ITSN1‐2) exacerbates inflammation and promotes T‐helper (Th) cell differentiation, also serves as a biomarker in critical illness diseases. However, its clinical role in sepsis remains obscure. Hence, the study aimed to explore the relationship of lnc‐ITSN1‐2 with Th cells, inflammation, disease severity, multiple organ dysfunction, and mortality risk in sepsis.MethodsPeripheral blood mononuclear cells (PBMC) were isolated from 95 sepsis patients and 50 health controls, followed by lnc‐ITSN1‐2 evaluation using RT‐qPCR. PBMC Th1, Th17 cells and their secreted cytokines in serum were detected by flow cytometry and ELISA, respectively.ResultsLnc‐ITSN1‐2 in sepsis patients was higher than it in health controls (Z = −7.328, p < 0.001). Lnc‐ITSN1‐2 correlated with increased interferon‐gamma (p = 0.009), Th17 cells (p = 0.022), and interleukin‐17A (p = 0.006), but not Th1 cells (p = 0.169) in sepsis patients. Moreover, lnc‐ITSN1‐2 had a positive connection with C‐reactive protein (p = 0.001), acute pathologic and chronic health evaluation (APACHE) II (p = 0.024), and sequential organ failure assessment (SOFA) scores (p = 0.022). Regarding SOFA subscales, lnc‐ITSN1‐2 linked with elevated respiratory system score (p = 0.005), cardiovascular system score (p = 0.007), and renal system score (p = 0.004) but no other subscales. Besides, lnc‐ITSN1‐2 had an increasing trend, but no statistical difference, in septic deaths compared to survivors (Z = −1.852, p = 0.064).ConclusionLnc‐ITSN1‐2 reflects sepsis progression and unfavorable prognosis to some extent, which may serve as a potential biomarker to improve the management of sepsis patients.

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.

In vivo evaluation of the protective effects of arjunolic acid against lipopolysaccharide-induced septic myocardial injury.

Lipopolysaccharide (LPS) is a glycolipid component of the cell wall of Gram-negative bacteria, which induces multiple organ dysfunctions, eventually leading to septic shock and death. Arjunolic acid (AA) has been shown to have therapeutic benefits against various organ pathophysiologies, although its role in sepsis remains unclear. Here, we evaluated the effects of AA on LPS-induced free radical production and cardiotoxicity. Male albino mice were allocated to four groups: normal, 1.5 µg/30 g b.w. of LPS (LPS), 20 mg/kg b.w. AA with LPS (AA+LPS) and 20 mg/kg b.w. of AA (AA). Subsequently, blood and heart samples were harvested for biochemical and histopathological examinations. Pretreatment with AA attenuated LPS-induced increased serum levels of cardiac troponin I, lactate dehydrogenase and creatine kinase. In the meantime, AA pretreatment before LPS resulted in a significant increase in endogenous antioxidants (superoxide dismutase, catalase, glutathione peroxidase and reduced glutathione) and a significant decrease in the level of lipid peroxidation product (malondialdehyde) in the heart as compared to the LPS group, while cardiac cytochrome c activity were significantly increased. In addition, in the AA-pretreated mice, C-reactive protein and proinflammatory cytokines (interlukin-1 and tumor necrosis factor-alpha) were significantly reduced, and anti-inflammatory cytokines (interleukin-4 and -10) were significantly increased in cardiac tissues as compared to the LPS-treated animals. Furthermore, prior administration of AA to LPS exposed mice led to a significant a significant decrease in heart caspase-3, -8, and -9 as compared to the LPS group. Interestingly, AA was also able to improve LPS-induced histopathological changes in the cardiomyocytes. In conclusion, these in vivo findings indicate that AA may be a promising cardioprotective agent against LPS-stimulated cardiotoxicity, at least in part, through upregulation of cardiac antioxidants, reduction of lipid peroxidation, and inhibition of inflammation and cardiac cell death.

Exosomes derived from the blood of patients with sepsis regulate apoptosis and aerobic glycolysis in human myocardial cells via the hsa‑miR‑1262/SLC2A1 signaling pathway.

Myocardial injury occurs in the majority of patients with sepsis and is associated with early mortality. MicroRNAs (miRs) transported by exosomes have been implicated in numerous diseases, such as tumors, acute myocardial infarction and cardiovascular disease. Human serum albumin (hsa)‑miR‑1262 has been shown to serve a role in sepsis; however, its role in exosomes isolated from patients with sepsis and septic myocardial injury remains unclear. In the present study, serum exosomes were isolated via ultracentrifugation. Solute carrier family2 member1 (SLC2A1), an essential mediator in energy metabolism, was silenced and overexpressed in the human myocardial AC16 cell line using lentiviral plasmids containing either SLC2A1‑targeting short interfering RNAs or SLC2A1 cDNA, respectively. Cell apoptosis was analyzed using flow cytometry, and the extracellular acidification rate and oxygen consumption rate of AC16 cells were determined using an XFe24 Extracellular Flux Analyzer. Furthermore, the dual‑luciferase reporter assay was used to evaluate the interaction between hsa‑miR‑1262 and SLC2A1. Finally, reverse transcription‑quantitative PCR and western blotting were used to evaluate gene and protein expression levels, respectively. Exosomes isolated from the blood of patients with sepsis (Sepsis‑exo) markedly reduced aerobic glycolysis activity, but significantly promoted the apoptosis of human AC16 cells in a time‑dependent manner. Moreover, Sepsis‑exo significantly increased hsa‑miR‑1262 expression levels, but significantly decreased SLC2A1 mRNA expression levels in a time‑dependent manner. Bioinformatics analysis indicated that hsa‑miR‑1262 bound to the 3'untranslated region of SLC2A1 to negatively regulate its expression. The silencing of SLC2A1 promoted apoptosis and suppressed glycolysis in AC16 cells, whereas SLC2A1 overexpression resulted in the opposite effects. Therefore, the present study demonstrated that exosomes derived from patients with sepsis may inhibit glycolysis and promote the apoptosis of human myocardial cells through exosomal hsa‑miR‑1262 via its target SLC2A1. These findings highlighted the importance of the hsa‑miR‑1262/SLC2A1 signaling pathway in septic myocardial injury and provided novel insights into therapeutic strategies for septic myocardial depression.

Sepsis and Septic Shock: Evolving Evidence, Evolving Paradigms.

Sepsis and septic shock represent important infection-related medical emergencies that result in significant morbidity and mortality. The prevalence and microbiology of these processes are evolving. Nonetheless, timely and appropriate antibiotic therapy continues to represent the most important determinant of survival. Recent trials have clarified that crystalloids are preferred for initial resuscitation, and balanced crystalloids appear superior to 0.9% saline. Controversy remains regarding not only the rate and rapidity of fluid resuscitation but also about the timing and use of vasopressors to maintain blood pressure. While some newer alternative vasopressors may have a role in sepsis, more evidence supporting their use is required. Conflicting data exist regarding the impact of corticosteroids on mortality in septic shock. However, these reports indicate that adjunctive hydrocortisone can lead to more rapid shock reversal.

TNFAIP8 modulates the survival and immune activity of Th17 cells via p53/ p21/ MDM2 pathway after acute insult

Th17 cells induced immunosuppression plays a vital role in sepsis. As a member of the tumor necrosis factor α induced protein 8 (TNFAIP8) family, TNFAIP8 is associated with different physiopathological conditions with immunological responses. However, its potential roles in regulating Th17 cells after the acute insult have not been fully elucidated. In this study, sepsis was induced by cecal ligation and puncture (CLP) in the male adult C57BL/6 mice. The stable TNFAIP8 knockdown (KD) Th17 cells were established by infecting with lentivirus carrying TNFAIP8-specific shRNA. CCK-8 assay was conducted to evaluate Th17 cell proliferation, and Annexin V/7-AAD assay was applied for apoptosis measurement by flow cytometry. The alterations of p53/ p21/ MDM2 pathway were assessed by Western blot. We observed that a high TNFAIP8 expression level was related to acute injury in septic mice. TNFAIP8 silencing suppressed Th17 cell proliferation and cytokine production in vivo and in vitro. In addition, TNFAIP8 KD increased Th17 cell apoptosis in septic mice. Furthermore, TNFAIP8 seems to affect the immune function of Th17 cells by regulating p53/ p21/ MDM2 signaling processes. We found that TNFAIP8 KD caused the up-regulation of P21 and MDM2, and also elevated p53 protein level during sepsis. Pharmacological inhibition of p53 partially rescued cell proliferation and apoptotic effects of TNFAIP8 KD. In summary, our work suggests that TNFAIP8 modulates the survival and immune function of Th17 cells after acute insult, which was possibly mediated through the p53/ p21/ MDM2 pathway.

Impact of Sepsis on High-Density Lipoprotein Metabolism.

Background: High-density lipoproteins (HDL) are thought to play a protective role in sepsis through several mechanisms, such as promotion of steroid synthesis, clearing bacterial toxins, protection of the endothelial barrier, and antioxidant/inflammatory activities. However, HDL levels decline rapidly during sepsis, but the contributing mechanisms are poorly understood. Methods/Aim: In the present study, we investigated enzymes involved in lipoprotein metabolism in sepsis and non-sepsis patients admitted to the intensive care unit (ICU). Results: In 53 ICU sepsis and 25 ICU non-sepsis patients, we observed significant differences in several enzymes involved in lipoprotein metabolism. Lecithin-cholesterol acyl transferase (LCAT) activity, LCAT concentration, and cholesteryl transfer protein (CETP) activity were significantly lower, whereas phospholipid transfer activity protein (PLTP) and endothelial lipase (EL) were significantly higher in sepsis patients compared to non-sepsis patients. In addition, serum amyloid A (SAA) levels were increased 10-fold in sepsis patients compared with non-sepsis patients. Furthermore, we found that LCAT activity was significantly associated with ICU and 28-day mortality whereas SAA levels, representing a strong inflammatory marker, did not associate with mortality outcomes. Conclusion: We provide novel data on the rapid and robust changes in HDL metabolism during sepsis. Our results clearly highlight the critical role of specific metabolic pathways and enzymes in sepsis pathophysiology that may lead to novel therapeutics.

The prognostic value of peripheral ischemic microvascular reserve in sepsis is not related to calcitonin gene-related peptide or substance P

OBJECTIVE: To evaluate the mechanisms attributed to the prognostic value of peripheral ischemic microvascular reserve in patients with sepsis. METHODS: This observational cohort study enrolled 46 consecutive septic patients in the intensive care unit between November 2020 and October 2021. After fluid resuscitation, the peripheral ischemic microvascular reserve was evaluated using the association of postocclusion reactive hyperemia with the peripheral perfusion index. Additionally, peripheral venous blood samples were used to evaluate the neuropeptide calcitonin gene-related peptide and substance P levels in the upper limb before and immediately after postocclusion reactive hyperemia RESULTS: There was no statistically significant correlation (p > 0.05) between basal values (pg/mL) or variations from neuropeptide levels (%) and the peripheral ischemic microvascular reserve (%). CONCLUSION: Although calcitonin gene-related peptide and substance P may have a prognostic role in sepsis, these neuropeptides do not appear to contribute to peripheral ischemic microvascular reserve.

Impairment of antigen-presenting function of peripheral γδ T cells in patients with sepsis

Impairment of antigen-presenting functions is a key mechanism contributing to sepsis-induced immunosuppression. Recently, γδ T cells have been demonstrated as professional antigen-presenting cells (APCs); however, their role in sepsis remains unknown. In this in vitro study, the APC function of human peripheral γδ T cells was assessed using samples collected from 42 patients with sepsis and 27 age-matched healthy controls. The APC-related markers HLA-DR, CD27, CD80, and CCR7 on fresh γδT cells were significantly higher in patients with sepsis compared with matched controls; however, they responded poorly to 4-hydroxy-3-methyl-2-butenyl pyrophosphate (HMBPP) stimulation, characterized by the deactivation of these APC markers and impaired proliferation. Furthermore, the adhesion function of γδ T cells, essential for antigen presentation, was greatly reduced in patients with sepsis; for instance, in co-cultures with green fluorescent protein-expressing Escherichia coli, HMBPP-activated γδT cells from healthy individuals adhered to E. coli efficiently, whereas no such phenomenon was observed with respect to γδT cells from patients with sepsis. In line with these results, in co-cultures with isolated CD4+ αβ T cells, HMBPP-activated γδT cells of healthy individuals promoted the efficient proliferation of CD4+ αβ T cells, whereas γδT cells from patients with sepsis did not do so. In conclusion, our findings show that the antigen-presenting function of γδT cells is severely impaired in patients with sepsis and the mechanisms behind need further study.

Long noncoding RNAs Colorectal Neoplasia Differentially Expressed and taurine-upregulated gene 1 are downregulated in sepsis and positively regulate each other to suppress the apoptosis of cardiomyocytes

ABSTRACT Long noncoding RNAs (lncRNAs) Colorectal Neoplasia Differentially Expressed (CRNDE) and taurine-upregulated gene 1 (TUG1) play similar roles in sepsis, indicating the existence of the crosstalk between them. Sepsis is a major cause of injuries in heart, which are related to high mortality rates. This study was therefore carried out to analyze the potential crosstalk between CRNDE and TUG1 in sepsis, with a focus on sepsis-induced cell apoptosis in heart. Expression of CRNDE and TUG1 was analyzed with RT-qPCR. Correlations between them were analyzed by Pearson’s correlation coefficient. CRNDE and TUG1 were overexpressed in cardiomyocytes to determine the relationship between them. The roles of CRNDE and TUG1 in regulating the apoptosis of cardiomyocytes were explored by cell apoptosis assay. We found that both CRNDE and TUG1 were downregulated in sepsis. In cardiomyocytes, LPS treatment resulted in the downregulation of CRNDE and TUG1. Overexpression of CRNDE and TUG1 in cardiomyocytes increased the expression levels of each other. Under lipopolysaccharide (LPS) treatment, decreased apoptosis rates of cardiomyocytes were observed after CRNDE and TUG1 overexpression. CRNDE and TUG1 co-overexpression showed a stronger effect. In conclusion, CRNDE and TUG1 are downregulated in sepsis and they positively regulate each other to suppress the apoptosis of cardiomyocytes.

Potential regulatory role of long non-coding RNA-microRNA-mRNA axis in sepsis

Sepsis is a life-threatening multiple organ dysfunction disease with high mortality and has become leading causes of death affecting intensive care unit (ICU) patients. Both long non-coding RNA (lncRNA) and microRNA (miRNA) are involved in the pathophysiological process of sepsis and can regulate the inflammatory response, both of which could be used as important diagnostic indicators and therapeutic targets of sepsis. The interaction among lncRNA, miRNA and mRNA plays an important role in sepsis and multiple organ dysfunction. This paper reviewed the regulatory relationship of lncRNA, miRNA and mRNA, as well as the regulatory role of lncRNA-miRNA-mRNA axis in inflammatory immune response and multiple organ dysfunction syndrome in sepsis, to provide new targets and strategies for the treatment of sepsis and organ dysfunction.

Contributory Role of BLT2 in the Production of Proinflammatory Cytokines in Cecal Ligation and Puncture-Induced Sepsis.

BLT2 is a low-affinity receptor for leukotriene B4, a potent lipid mediator of inflammation generated from arachidonic acid via the 5-lipoxygenase pathway. The aim of this study was to investigate whether BLT2 plays any role in sepsis, a systemic inflammatory response syndrome caused by infection. A murine model of cecal ligation and puncture (CLP)-induced sepsis was used to evaluate the role of BLT2 in septic inflammation. In the present study, we observed that the levels of ligands for BLT2 (LTB4 [leukotriene B4] and 12(S)-HETE [12(S)-hydroxyeicosatetraenoic acid]) were significantly increased in the peritoneal lavage fluid and serum from mice with CLP-induced sepsis. We also observed that the levels of BLT2 as well as 5-lipoxygenase (5-LO) and 12-LO, which are synthesizing enzymes for LTB4 and 12(S)-HETE, were significantly increased in lung and liver tissues in the CLP mouse model. Blockade of BLT2 markedly suppressed the production of sepsis-associated cytokines (IL-6 [interleukin-6], TNF-α[[tumor necrosis factor alpha], and IL-1β [interleukin-1β] as well as IL-17 [interleukin-17]) and alleviated lung inflammation in the CLP group. Taken together, our results suggest that BLT2 cascade contributes to lung inflammation in CLP-induced sepsis by mediating the production of inflammatory cytokines. These findings suggest that BLT2 may be a potential therapeutic target for sepsis patients.

Targeting S100A9 Reduces Neutrophil Recruitment, Inflammation and Lung Damage in Abdominal Sepsis.

S100A9, a pro-inflammatory alarmin, is up-regulated in inflamed tissues. However, the role of S100A9 in regulating neutrophil activation, inflammation and lung damage in sepsis is not known. Herein, we hypothesized that blocking S100A9 function may attenuate neutrophil recruitment in septic lung injury. Male C57BL/6 mice were pretreated with the S100A9 inhibitor ABR-238901 (10 mg/kg), prior to cercal ligation and puncture (CLP). Bronchoalveolar lavage fluid (BALF) and lung tissue were harvested for analysis of neutrophil infiltration as well as edema and CXC chemokine production. Blood was collected for analysis of membrane-activated complex-1 (Mac-1) expression on neutrophils as well as CXC chemokines and IL-6 in plasma. Induction of CLP markedly increased plasma levels of S100A9. ABR-238901 decreased CLP-induced neutrophil infiltration and edema formation in the lung. In addition, inhibition of S100A9 decreased the CLP-induced up-regulation of Mac-1 on neutrophils. Administration of ABR-238901 also inhibited the CLP-induced increase of CXCL-1, CXCL-2 and IL-6 in plasma and lungs. Our results suggest that S100A9 promotes neutrophil activation and pulmonary accumulation in sepsis. Targeting S100A9 function decreased formation of CXC chemokines in circulation and lungs and attenuated sepsis-induced lung damage. These novel findings suggest that S100A9 plays an important pro-inflammatory role in sepsis and could be a useful target to protect against the excessive inflammation and lung damage associated with the disease.