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

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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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.

Original languageEnglish (US)
Article number106442
JournaliScience
Volume26
Issue number4
DOIs
StatePublished - Apr 21 2023

Keywords

  • Immunology
  • Molecular mechanism of gene regulation
  • Transcriptomics

ASJC Scopus subject areas

  • General

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