The Agonists of Formyl Peptide Receptors Prevent Development of Severe Sepsis after Microbial Infection

Abstract

Severe sepsis, a principal cause of death in intensive care units, occurs when host immune defenses fail to combat invading microbes. In this paper, we report that the administration of peptide agonists of formyl peptide receptors, including Trp-Lys-Tyr-Met-Val-D-Met (WKYMVm), protected against death by enhanced bactericidal activity and inhibition of vital organ inflammation and immune cell apoptosis in a cecal ligation and puncture (CLP) sepsis mouse model. The administration of WKYMVm also enhanced the production of type 1 (IFN-gamma and IL-12) and type 17 (IL-17 and TGF-beta) cytokines in CLP mice. In contrast, the administration of WKYMVm inhibited the production of proinflammatory cytokines (TNF-alpha, IL-1 beta, and IL-6) in the CLP mice. The therapeutic and bactericidal effects of WKYMVm were partly reversed in IFN-gamma-deficient mice, whereas target organ inflammation was not. Meanwhile, the therapeutic and anti-inflammatory effects of WKYMVm were partly reversed in IL-17-deficient mice. In addition, the administration of WKYMVm also enhanced type 1 and type 17 Th cell responses in mice sensitized with LPS plus Ags. These results suggest that the agonists of formyl peptide receptors effectively prevent development of severe sepsis following microbial infection partly via augmentation of type 1 and type 17 immune responses. The Journal of Immunology, 2010, 185: 4302-4310.