Therapeutic S100A8/A9 blockade inhibits myocardial and systemic inflammation and mitigates sepsis-induced myocardial dysfunction

Abstract

Background and Aims The triggering factors of sepsis-induced myocardial dysfunction (SIMD) are poorly understood and are not addressed by current treatments. S100A8/A9 is a pro-inflammatory alarmin abundantly secreted by activated neutrophils during infection and inflammation. We investigated the efficacy of S100A8/A9 blockade as a potential new treatment in SIMD. Methods The relationship between plasma S100A8/A9 and cardiac dysfunction was assessed in a cohort of 62 patients with severe sepsis admitted to the intensive care unit of Linköping University Hospital, Sweden. We used S100A8/A9 blockade with the small-molecule inhibitor ABR-238901 and S100A9−/− mice for therapeutic and mechanistic studies on endotoxemia-induced cardiac dysfunction in mice. Results In sepsis patients, elevated plasma S100A8/A9 was associated with left-ventricular (LV) systolic dysfunction and increased SOFA score. In wild-type mice, 5 mg/kg of bacterial lipopolysaccharide (LPS) induced rapid plasma S100A8/A9 increase and acute LV dysfunction. Two ABR-238901 doses (30 mg/kg) administered intraperitoneally with a 6 h interval, starting directly after LPS or at a later time-point when LV dysfunction is fully established, efficiently prevented and reversed the phenotype, respectively. In contrast, dexamethasone did not improve cardiac function compared to PBS-treated endotoxemic controls. S100A8/A9 inhibition potently reduced systemic levels of inflammatory mediators, prevented upregulation of inflammatory genes and restored mitochondrial function in the myocardium. The S100A9−/− mice were protected against LPS-induced LV dysfunction to an extent comparable with pharmacologic S100A8/A9 blockade. The ABR-238901 treatment did not induce an additional improvement of LV function in the S100A9−/− mice, confirming target specificity. Conclusion Elevated S100A8/A9 is associated with the development of LV dysfunction in severe sepsis patients and in a mouse model of endotoxemia. Pharmacological blockade of S100A8/A9 with ABR-238901 has potent anti-inflammatory effects, mitigates myocardial dysfunction and might represent a novel therapeutic strategy for patients with severe sepsis. Graphical Abstract

Increasing plasma calprotectin (S100A8/A9) is associated with 12-month mortality and unfavourable functional outcome in critically ill COVID-19 patients

“…These findings support the hypothesis that activated neutrophils and calprotectin play direct pathogenic roles in SARS-CoV-2-induced disease and might be targeted to modulate the exaggerated immune response. In further support of this hypothesis, it has previously been shown that calprotectin blockade potently reduces systemic inflammation and mitigates cardiac failure in endotoxin-induced sepsis [ 31 ].…”

Metformin Mitigates Sepsis-Induced Acute Lung Injury and Inflammation in Young Mice by Suppressing the S100A8/A9-NLRP3-IL-1β Signaling Pathway

“… 56 A previous study indicated that S100A8/A9 in the plasma of patients following ALI brought about by sepsis or pneumonia significantly elevated as compared with healthy controls. 57 S100A8/A9 has been established to be one of the most distinctive DAMPs in sepsis, 58 , 59 which interacts with cell surface receptors on various immune cells, platelets, endothelial cells, and intracellular PRRs, exerting detrimental impacts on sepsis pathogenesis. 43 Specifically, activation of the S100A8/A9 complex through binding with TLR4 can induce pro-inflammatory cytokine production and promote not only recruitment but also activation of immune cells, ultimately leading to tissue damage and dysfunctions of organs in sepsis.…”

Reply to “Potential confounders in linking elevated S100A8/A9 to left ventricular dysfunction in septic shock patients”

“…Since the molecular weight of the S100A8/A9 heterodimer (24 kDa) is lower than the cutoff value of the extracorporeal purification membrane (35–40 kDa), the use of RRT might partly remove S100A8/A9 from the circulation, leading to falsely low values of the protein in plasma. The authors of the comment argue that this might have led to erroneous conclusions regarding the positive relationship between elevated plasma S100A8/A9 and the development of sepsis-induced myocardial dysfunction (SIMD) demonstrated by our study [ 2 ]. The concern regarding the influence of RRT on biomarker values in the context of sepsis is not specific for S100A8/A9 and has previously been expressed by Honoré et al .…”

“…We would like to address the comments by Honoré et al . [ 1 ] referring to our recently published paper “Therapeutic S100A8/A9 blockade inhibits myocardial and systemic inflammation and mitigates sepsis‑induced myocardial dysfunction” [ 2 ].…”

“…We agree that biomarker washout by RRT is an important factor that might impact both clinical studies and clinical practice, regardless of the initial pathology leading to renal failure. However, we would like to stress that in our study, S100A8/A9 was measured in plasma collected within 12 h from admission to the intensive care unit (ICU), as mentioned in the Methods section [ 2 ]. At this early time point, none of the sepsis patients included in the cohort had received RRT.…”