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

Abstract

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.

• Authors: Diego R Coelho, Flavio R Palma, Veronica Paviani, Katy M LaFond, Yunping Huang, Dongmei Wang, Brian Wray, Sridhar Rao, Feng Yue, Marcelo G Bonini, Benjamin N Gantner
• Journal: iScience (iScience) Vol. 26 Issue 4 Pg. 106442 (Apr 21 2023) ISSN: 2589-0042 [Electronic] United States
• PMID: 37020964 (Publication Type: Journal Article)
• Copyright: © 2023 The Authors.