Ribonuclease inhibitor 1 emerges as a potential biomarker and modulates inflammation and iron homeostasis in sepsis.

Sepsis, marked by organ dysfunction, necessitates reliable biomarkers. Ribonuclease inhibitor 1 (RNH1), a ribonuclease (RNase) inhibitor, emerged as a potential biomarker for acute kidney injury and mortality in thoracoabdominal aortic aneurysm patients. Our study investigates RNH1 dynamics in sepsis, its links to mortality and organ dysfunction, and the interplay with RNase 1 and RNase 5. Furthermore, we explore RNH1 as a therapeutic target in sepsis-related processes like inflammation, non-canonical inflammasome activation, and iron homeostasis. We showed that RNH1 levels are significantly higher in deceased patients compared to sepsis survivors and correlate with creatine kinase, aspartate and alanine transaminase, bilirubin, serum creatinine and RNase 5, but not RNase 1. RNH1 mitigated LPS-induced TNFα and RNase 5 secretion, and relative mRNA expression of ferroptosis-associated genes HMOX1, FTH1 and HAMP in PBMCs. Monocytes were identified as the predominant type of LPS-positive PBMCs. Exogenous RNH1 attenuated LPS-induced CASP5 expression, while increasing IL-1ß secretion in PBMCs and THP-1 macrophages. As RNH1 has contradictory effects on inflammation and non-canonical inflammasome activation, its use as a therapeutic agent is limited. However, RNH1 levels may play a central role in iron homeostasis during sepsis, supporting our clinical observations. Hence, RNH1 shows promise as biomarkers for renal and hepatic dysfunction and hepatocyte injury, and may be useful in predicting the outcome of septic patients.

A Potential Association between Ribonuclease 1 Dynamics in the Blood and the Outcome in COVID-19 Patients.

The COVID-19 pandemic caused by the new SARS-CoV-2 coronavirus is the most recent and well-known outbreak of a coronavirus. RNase 1 is a small endogenous antimicrobial polypeptide that possesses antiviral activity against viral diseases. In this study, we investigated a potential association between ribonuclease 1 and the outcome in COVID-19 patients and the impact of increased and decreased RNase 1 levels serum during the course of the disease. Therefore, two patient populations, Cohort A (n = 35) and B (n = 80), were subclassified into two groups, in which the RNase 1 concentration increased or decreased from time point one to time point two. We show that the RNase 1 serum levels significantly increased in the increasing group of both cohorts (p = 0.0171; p < 0.0001). We detect that patients in the increasing group who died had significantly higher RNase 1 serum levels at both time points in Cohort A (p = 0.0170; p = 0.0393) and Cohort B (p = 0.0253; p = 0.0034) than patients who survived. Additionally, we measured a significant correlation of RNase 1 serum levels with serum creatinine as well as creatinine clearance in the increasing and decreasing group at both time points of Cohort A. Based on these results, there is now good evidence that RNase 1 may play a role in renal dysfunction associated with ICU COVID-19 patients and that increasing RNase 1 serum level may be a potential biomarker to predict outcome in COVID-19 patients.

DAMPs Released from Proinflammatory Macrophages Induce Inflammation in Cardiomyocytes via Activation of TLR4 and TNFR.

Cardiac dysfunction is a life-threatening complication in sepsis. Upon infection and cardiac stress, the cardiac macrophage population expands. Recruited macrophages exhibit a predominantly proinflammatory phenotype and release danger-associated molecular patterns (DAMPs) that contribute to cardiac dysfunction. However, the underlying pathomechanisms are highly complex and not fully understood. Here, we utilized an indirect macrophage-cardiomyocyte co-culture model to study the effects of proinflammatory macrophages on the activation of different cardiac receptors (TLR3, TLR4, and TNFR) and their role in cardiac inflammation and caspase-3/7 activation. The stimulation of cardiomyocytes with conditioned medium of LPS-stimulated macrophages resulted in elevated IL-6 protein concentrations and relative IL-6 and TNFα mRNA levels. Conditioned medium from LPS-stimulated macrophages also induced NFκB translocation and increased caspase-3/7 activation in cardiomyocytes. Analyzing the role of different cardiac receptors, we found that TLR4 and TNFR inhibition reduces cardiac inflammation and that the inhibition of TNFR prevents NFκB translocation into the nuclei of cardiomyocytes, induced by exposure to conditioned medium of proinflammatory macrophages. Moreover, we demonstrated that TLR3 inhibition reduces macrophage-mediated caspase-3/7 activation. Our results suggest that the immune response of macrophages under inflammatory conditions leads to the release of DAMPs, such as eRNA and cytokines, which in turn induce cardiomyocyte dysfunction. Thus, the data obtained in this study contribute to a better understanding of the pathophysiological mechanisms of cardiac dysfunction.