SOCS1 regulates a subset of NFκB-target genes through direct chromatin binding and defines macrophage functional phenotypes. iScience 2023 Apr 21;26(4):106442
Date
04/07/2023Pubmed ID
37020964Pubmed Central ID
PMC10068561DOI
10.1016/j.isci.2023.106442Scopus ID
2-s2.0-85151424842 (requires institutional sign-in at Scopus site) 5 CitationsAbstract
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.
Author List
Coelho DR, Palma FR, Paviani V, LaFond KM, Huang Y, Wang D, Wray B, Rao S, Yue F, Bonini MG, Gantner BNAuthors
Benjamin N. Gantner PhD Assistant Professor in the Medicine department at Medical College of WisconsinSridhar Rao MD, PhD Associate Professor in the Pediatrics department at Medical College of Wisconsin
