Methionine sulfoxide reductase A protects against lipopolysaccharide-induced septic shock via negative regulation of the proinflammatory responses

Methionine sulfoxide reductase A (MsrA) is a major antioxidant enzyme that specifically catalyzes the reduction of methionine S-sulfoxide. In this study, we used MsrA gene-knockout (MsrA-1) mice and bone marrow-derived macrophages (BMDMs) to investigate the role of MsrA in the regulation of inflammatory responses induced by lipopolysaccharide (LPS). MsrA I mice were more susceptible to LPSinduced lethal shock than wild-type (MsrA I) mice. Serum levels of the proinflammatory cytokines IL-6 and TNE-ce induced by LPS were higher in MsrA l than in MsrA(-/-) mice. MsrA deficiency in the BMDMs also increased the LPS-induced cytotoxicity as well as TNF-cc level. Basal and LPS-induced reactive oxygen species (ROS) levels were higher in MsrA I than in MsrA(-/-) BMDMs. Phosphorylation levels of p38, JNK, and ERK were higher in MsrA-1 than in MsrA(-/-) BMDMs in response to LPS, suggesting that MsrA deficiency increases MAPK activation. Furthermore, MsrA deficiency increased the expression and nuclear translocation of NF-KB and the expression of inducible nitric oxide synthase, a target gene of NE-KB, in response to LPS. Taken together, our results suggest that MsrA protects against LPS-induced septic shock, and negatively regulates proinflammatory responses via inhibition of the ROS MAPK NF-KB signaling pathways. (C) 2017 Elsevier Inc. All rights reserved.