Daily Sepsis Research Analysis

Itaconate is a Krebs cycle-derived metabolite whose production is catalyzed by immune response gene 1 (IRG1). As an anti-inflammatory metabolite, itaconate primarily exerts its effects through alkylation of target proteins. Previous studies have identified the JAK-STAT pathway as a key therapeutic target in sepsis. Interestingly, we report that itaconate, a metabolite significantly upregulated during metabolic reprogramming, suppresses type I interferon (IFN-I) signaling. Exogenous supplementation with the itaconate derivative 4-octyl itaconate (4OI) inhibits the JAK-STAT pathway. Mechanistically, 4OI inhibits the binding of tyrosine kinase 2 (TYK2) to IFNAR1 and JAK1 to IFNAR2 by alkylating cysteine 192 in TYK2 and cysteine 189 in JAK1. Our research has identified the crucial role of itaconate produced by the tricarboxylic acid (TCA) cycle in restricting JAK-STAT signal transduction, thereby linking metabolism and innate immunity, and provides a theoretical basis for the therapeutic application of 4OI in sepsis.

BACKGROUND AND PURPOSE: Septic cardiomyopathy (SCM) is a significant contributor to mortality among septic patients, but effective therapeutic strategies are still lacking. Deubiquitinating enzymes (DUBs) such as ……. function as crucial regulators of protein ubiquitination and may play a fundamental role in the pathogenesis of heart diseases. EXPERIMENTAL APPROACH: In two models of SCM induced by lipopolysaccharide (LPS) or caecal ligation and puncture (CLP) in C57BL/6J mice, the differential expression of DUB genes was identified by transcriptome sequencing. Sepsis models were established through LPS injection or CLP surgery in both cardiomyocyte-specific YOD1 knockout (YOD1CKO) mice and littermate wild-type (Yod1 KEY RESULTS: Expression of DUB YOD1 was up-regulated in cardiac tissues of LPS/CLP-induced septic mice. Cardiomyocyte-derived YOD1 deficiency alleviated SCM and protected cardiac function in LPS/CLP-challenged mice. Mechanistically, YOD1 interacted with the inflammasome NLRP3 and then deubiquitinated the K48 ubiquitin chain on the NLRP3 protein by its active site H262, thereby blocking degradation of NLRP3 in cardiomyocytes. Consequently, NLRP3 activation and NLRP3-driven pyroptosis were increased in both cardiomyocytes and septic mouse hearts. Inhibition of NLRP3 counteracted the protective effects of YOD1 knockout in SCM mice. Furthermore, pharmacological inhibition of YOD1 improved myocardial injury elicited by CLP in mice. CONCLUSION AND IMPLICATIONS: Cardiomyocyte YOD1 mediated SCM by deubiquitinating NLRP3 and promoting NLRP3-driven pyroptosis. Our results have revealed a new YOD1-NLRP3 axis in cardiomyocytes and identified YOD1 as a novel therapeutic target for treating SCM.

BACKGROUND: Sepsis is characterised as life-threatening organ dysfunction due to a dysregulated host response to infection. It carries high mortality and is a major public health issue globally. Among adults presenting to the emergency department with features of suspected sepsis, rapid and accurate differentiation of those at high risk for prompt delivery of key therapies and escalation of care may improve outcomes. OBJECTIVES: To conduct a comprehensive evidence synthesis assessing the clinical utility of established and novel biomarkers - used individually or in combination - for predicting the risk of death or clinical deterioration in adults with clinically suspected sepsis presenting to the emergency department. DESIGN AND METHODS: Search strategies were designed to identify English-language studies published between 2013 and 2023 evaluating biomarker performance to predict mortality or clinical deterioration in adults with suspected sepsis. Eligible studies had to evaluate biomarker performance in patients with clinically suspected sepsis (as defined by study authors) at emergency department presentation. Outcomes of interest included all-cause mortality, critical care admission, septic shock and organ failure. A comprehensive search was conducted across multiple databases, including MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials (search date 5 July 2023). For each biomarker, used alone or in combination, risk ratios, hazard ratios, odds ratios and area under the receiver-operating characteristics curve values were extracted. Subgroup analyses were planned to compare patients in terms of age, presence of comorbidities, National Health Service or other health systems, and biomarker assessment timing. Methodological quality was evaluated using the Quality in Prognostic Factor Studies tool. RESULTS: Of 1986 citations identified, 884 duplicates were removed, and 1102 were screened by title and abstract. Of the 430 full-text articles assessed, 377 were excluded as they did not meet the eligibility criteria, and 53 reports, related to 51 studies, were deemed suitable for inclusion. A total of 107 unique biomarkers or biomarker combinations were assessed across the included studies. However, due to limited data and clinical heterogeneity, only biomarkers commonly used in clinical practice (lactate, C-reactive protein and procalcitonin) were analysed through meta-analyses, and none effectively predicted adverse outcomes. Although novel biomarkers could not be pooled, several (Inflammatix Severity 2, mid-regional proadrenomedullin, neutrophil gelatinase-associated lipocalin, tyrosine kinase with immunoglobulin-like and epidermal growth factor-like domains 2, monocyte distribution width and neutrophil-to-lymphocyte ratio) showed potential for predicting mortality and admission to critical care. The predictive accuracy of these biomarkers improved when combined with other biomarkers and/or clinical scores. LIMITATIONS: There was considerable heterogeneity across included studies and insufficient data for meta-analysis of novel biomarkers. CONCLUSIONS: In emergency department patients with clinically suspected sepsis, lactate, C-reactive protein and procalcitonin did not effectively predict mortality or need for clinical care admission. However, some novel biomarkers showed promise for the prediction of these outcomes, particularly when combined with other biomarkers and/or commonly used clinical scores. FUTURE RESEARCH: Focusing on prospectively designed studies, there should be standardisation of biomarker thresholds, measurement timing and identification of participants to facilitate comparability across studies. Researchers should apply a clear and consistent definition of suspected sepsis. Adjusted and unadjusted analyses should be reported, accounting for critical variables. FUNDING: This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number NIHR159912. Sepsis is a common, serious and often fatal clinical condition that happens when the body responds in the wrong way to infection. People with sepsis do better when it is found early so that they can get antibiotics and fluids, and, when possible, surgical management of the infection source. However, patients often present to the emergency department with vague and non-specific symptoms and signs of possible sepsis. Therefore, identifying patients who are high risk and need intervention can be very difficult. Biomarkers are biological molecules that may increase or decrease in the blood, or other body fluids when a person is unwell. The best biomarkers would only appear when a specific disease was present, helping clinicians to diagnose the disease. Ideally, biomarker levels would be in line with the severity of the disease, which would guide treatment decisions. However, no perfect biomarker exists. When patients present to the emergency department with possible sepsis, we do not know whether biomarkers can reliably identify which patients are at risk of becoming seriously unwell or dying. We reviewed clinical studies from the past 11 years to find out if biomarkers measured in adults presenting to the emergency department with symptoms suspicious of sepsis can help recognition of those at a higher risk of becoming seriously ill or dying. Our review found that in patients with suspected sepsis, common biomarkers, such as C-reactive protein, procalcitonin and lactate, did not help to identify high-risk patients. However, newer biomarkers were promising, especially when biomarkers were combined or when biomarkers were used alongside clinical score. Nevertheless, there are still too few studies to make any recommendations for clinical practice. High-quality research is urgently needed to understand how these biomarkers work and how they could help in treating patients with possible sepsis in the emergency department.