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

• Published in: iScience Vol. 26; no. 4; p. 106442
• Main Authors: Coelho, Diego R., Palma, Flavio R., Paviani, Veronica, LaFond, Katy M., Huang, Yunping, Wang, Dongmei, Wray, Brian, Rao, Sridhar, Yue, Feng, Bonini, Marcelo G., Gantner, Benjamin N.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21-04-2023; Elsevier
• Subjects: Immunology; Molecular mechanism of gene regulation; Transcriptomics; Transcriptomics; Immunology; Molecular mechanism of gene regulation
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2023.106442

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.
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•SOCS1 is a critical negative regulator of p65 NF-κB in unactivated macrophages•SOCS1 binds to a subset of pro-inflammatory genes, suppressing their transcription•NO from NOS1 removes SOCS1, licensing maximal pro-inflammatory transcription•NOS1 deficiency increases a subset of suppressive pulmonary macrophages
Immunology; Molecular mechanism of gene regulation; Transcriptomics