LAUSR

Macrophages play a critical role in inflammation initiation, progression and resolution due to their capacity to assume both pro- and anti-inflammatory phenotypes. The molecular mechanisms that regulate these transitions are of great clinical interest but remain poorly understood. We discovered that suppressor of cytokine signaling-1, an enzyme that targets and degrades RelA, is susceptible to S-nitrosation on cisteines 147 and 179 specifically in the nucleus. Nitrosation in the nucleus is effected by nitric oxide synthase-1 (NOS1) in macrophages. Nitrosation of SOCS1 prevents its interaction with RelA, and the formation of the pro-inflammatory p65-p50 NFkB heterodimer. In NOS1 knockout macrophages, SOCS1 is not nitrosated upon activation of the inflammatory response leading to rapid degradation of RelA/p65 with the accumulation of p50. Accumulation of p50 promotes homodimerization (p50-p50) leading to anti-inflammatory gene transcription. Interestingly, transplantation of NOS1 knockout bone marrow-derived macrophages (BMDM) into the inflammation prone lungs of SOCS1fl/fl.LysMCre mice is protective against LPS-induced tissue injury. In addition, levels of pro-inflammatory cytokine production in these lungs are markedly reduced after LPS challenge suggesting NOS1KO BMDM have the capacity to suppress pro-inflammatory immune polarization and associated tissue injury in a model of chronic inflammatory lung disease. Overall our results indicate that SOCS1 acts as a switch between pro- and anti-inflammatory macrophage polarization regulated by NOS1-mediated nitrosation.