Sepsis, a severe medical condition when the body’s response to infection causes inflammation and organ dysfunction, remains a significant challenge for clinicians. While antimicrobial therapy and organ support are currently the best treatments available, no licensed treatments exist beyond these interventions.
As per a recent study published in PLOS Medicine, Interleukin 6 (IL-6), a key cytokine involved in the innate immune response to severe infections such as sepsis, has been identified as a potential target for therapeutic intervention. IL-6 contributes to adverse outcomes in sepsis through various pathophysiological processes, and its modulation represents an exciting opportunity for treating severe infections.
IL-6 is known to play an inflammatory role mediated by a trans-signaling mechanism. It binds to a soluble receptor form and subsequently interacts with membrane-bound signaling molecules in cells.
Monoclonal antibodies such as tocilizumab or sarilumab, which inhibit membrane-bound and soluble IL6R, have been successfully trialed in critically ill patients with COVID-19 and are now considered standard treatment. These drugs have been shown to reduce C-reactive protein (CRP) and other downstream inflammatory markers, benefiting patients with COVID-19.
Specific single nucleotide polymorphisms (SNPs) around and in the IL6R gene, which phenocopy IL6RA function, have been found to reduce the risk of becoming critically ill with COVID-19. These same IL6R variants have been used in Mendelian randomization (MR) studies to alter IL6R function and signaling, providing an available proxy of IL6RA therapy.
One specific SNP, rs2228145, has been extensively studied in the context of reduced IL-6 signaling and inflammation. A previous MR analysis suggested that reduced IL-6 signaling modeled using rs2228145 alone could reduce inflammation and the risk of coronary heart disease.
This finding has led to clinical trials of monoclonal antibodies targeting either IL6R or IL-6 to prevent coronary disease. This study found that blocking the signaling pathways of interleukin-6 (IL-6), a cytokine involved in the immune response, is likely protective against sepsis.
The research used data from UK Biobank, FinnGen, GenOSept, and GAiNS to determine that functional IL6R blockade was associated with potentially protective effects against short-term death in sepsis and critical care admission with sepsis.
The effect was similar to that seen in severe COVID-19, where IL6RA had already been shown to improve mortality. However, functional IL6R blockade increased infection susceptibility, matching trial and registry data.
The study also found evidence that IL6R blockade may be protective in critical illness in respiratory infection, where effect estimates were similar to those seen in sepsis and consistent with the COVID-19 data. The researchers suggested that IL6RA is a potentially broad therapeutic target for patients unwell with acute infection.