SOCS1 regulates a subset of NFκB-target genes through direct chromatin binding and defines macrophage functional phenotypes.

Suppressor of cytokine signaling-1 (SOCS1) exerts control over inflammation by targeting p65 nuclear factor-κB (NF-κB) for degradation in addition to its canonical role regulating cytokine signaling. We report here that SOCS1 does not operate on all p65 targets equally, instead localizing to a select subset of pro-inflammatory genes. Promoter-specific interactions of SOCS1 and p65 determine the subset of genes activated by NF-κB during systemic inflammation, with profound consequences for cytokine responses, immune cell mobilization, and tissue injury. Nitric oxide synthase-1 (NOS1)-derived nitric oxide (NO) is required and sufficient for the displacement of SOCS1 from chromatin, permitting full inflammatory transcription. Single-cell transcriptomic analysis of NOS1-deficient animals led to detection of a regulatory macrophage subset that exerts potent suppression on inflammatory cytokine responses and tissue remodeling. These results provide the first example of a redox-sensitive, gene-specific mechanism for converting macrophages from regulating inflammation to cells licensed to promote aggressive and potentially injurious inflammation.

Nitric oxide in cellular adaptation and disease.

Nitric oxide synthases are the major sources of nitric oxide, a critical signaling molecule involved in a wide range of cellular and physiological processes. These enzymes comprise a family of genes that are highly conserved across all eukaryotes. The three family members found in mammals are important for inter- and intra-cellular signaling in tissues that include the nervous system, the vasculature, the gut, skeletal muscle, and the immune system, among others. We summarize major advances in the understanding of biochemical and tissue-specific roles of nitric oxide synthases, with a focus on how these mechanisms enable tissue adaptation and health or dysfunction and disease. We highlight the unique mechanisms and processes of neuronal nitric oxide synthase, or NOS1. This was the first of these enzymes discovered in mammals, and yet much remains to be understood about this highly conserved and complex gene. We provide examples of two areas that will likely be of increasing importance in nitric oxide biology. These include the mechanisms by which these critical enzymes promote adaptation or disease by 1) coordinating communication by diverse cell types within a tissue and 2) directing cellular differentiation/activation decisions processes.