Apolipoprotein H as a Crucial Immunomodulatory Factor in Sepsis

Abstract

Abstract Background. Sepsis is a life-threatening acute organ dysfunction caused by a dysregulated immune response to infections. Apolipoprotein H (APOH) is an important plasma protein that regulates diverse biological processes. However, the role of APOH in the immunopathology of sepsis remains unidentified. Methods. APOH concentration was determined in pediatric patients with sepsis and healthy individuals. The effect of APOH on survival, organ injury, and inflammation were measured in an experimental sepsis model of cecal ligation and puncture (CLP). The possible mechanisms of APOH on anti-inflammation response were explored in PBMC, PM, BMDM and RAW 264.7 macrophages. Results. APOH concentration was significantly decreased in the patients with sepsis compared with those of healthy controls, and was negatively linked with severity and mortality of pediatric sepsis. Therapeutic administration of recombinant APOH protein reduced the mortality rate in mice with sepsis, alleviated organs injury and inhibited inflammation in mice with severe sepsis. Conversely, neutralizing APOH by anti-APOH monoclonal antibody led to an increased mortality rate, organs injury and inflammation in mice with nonsevere sepsis. Intriguingly, APOH had negligible influences on bacterial burden and the counts of neutrophils and macrophages in sepsis mice model, and bacterial phagocytosis and killing upon P. aeruginosa infection in PM, RAW 264.7 and PBMC cells. Mechanistic investigation in PM and RAW 264.7 cells indicated that APOH reshaped macrophage polarization by inhibiting M1 macrophage through suppression of toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) signaling pathway. Conclusion. This proof-of-concept study elucidated that APOH played an important role in the host defense response to sepsis and suggested a potential therapeutic role for APOH in the treatment of sepsis.