Immunopathogenesis of post-Sepsis immunosuppression

• Grant number: 21/08425-7
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: September 01, 2021
• End date: January 31, 2022
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: José Carlos Farias Alves Filho
• Grantee: Leonardo Pedrazza
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases, AP.CEPID

Abstract

Sepsis is a complex syndrome of infectious origin, causing an uncontrolled systemic inflammatory response. Sepsis has been a serious epidemiological problem for health systems around the world, both economically and socially. In 2017, an estimated 48.9 million incident cases of Sepsis were reported worldwide and 11 million Sepsis-related deaths were reported, representing 19.7% of all global deaths. Although advances in supportive care have reduced Sepsis mortality in recent decades, patients who survive severe Sepsis have a high number of readmissions and increased mortality as a consequence of recurrent infections. In fact, clinical and experimental studies indicate that Sepsis can cause an immunosuppressive state that is responsible for the increased susceptibility to secondary infections, mainly opportunistic. Evidence demonstrates that patients with septic shock have an increased frequency of circulating regulatory T cells (Treg) that correlates with immunosuppression. Another feature of Sepsis-induced immunosuppression is the overproduction of anti-inflammatory cytokines and immune cells related to apoptosis. Interleukin-10 (IL-10) is one of the most important anti-inflammatory cytokines. Previous research has reported that the higher plasma concentration of IL-10 contributed to a higher mortality from Sepsis. IL-10 receptors are members of the class II cytokine receptor family and are predominantly expressed on immune cells. The IL-10 receptor is composed of two subunits, IL-10RI, a ligand-binding subunit, and IL-10RII, an accessory subunit necessary for signal transduction. Due to its potent anti-inflammatory properties, IL-10 inhibits the nuclear translocation of the NFºB transcription factor and the subsequent synthesis of pro-inflammatory cytokines, and promotes mRNA degradation of pro-inflammatory cytokines. In this context, using a conditional knockout model for IL-10R, the aim of the study is to identify cellular mechanisms and the relevance of IL-10 regulation in post-Sepsis immunosuppression. (AU)