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

doi:10.1016/j.isci.2023.106442

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 journal › Article › peer-review

6 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 language	English (US)
Article number	106442
Journal	iScience
Volume	26
Issue number	4
DOIs	https://doi.org/10.1016/j.isci.2023.106442
State	Published - Apr 21 2023

Funding

The authors acknowledge funding from the U.S. Heart Lung and Blood Institute (NHLBI to M.G.B. and B.N.G.), R01HL163820 ; U.S. National Institute of Allergy and Infectious Diseases (NIAID to M.G.B.), RO1AI131267 ; U.S. National Cancer Institute (NCI to M.G.B.), R01CA216882 and U.S. National Institute of Environmental Health Sciences (NIEHS to M.G.B.), R01ES028149 . The authors also acknowledge funding from the Advancing a Healthier Wisconsin (to B.N.G. and M.G.B.) and funding from U.S. Department of Defense , Army Research Office grant # 72983 to M.G.B. and B.N.G. The authors thank Drs. Alexander Misharin and Scott Budinger (Northwestern University of Chicago) for helpful discussions.

Keywords

Immunology
Molecular mechanism of gene regulation
Transcriptomics

ASJC Scopus subject areas

General

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10.1016/j.isci.2023.106442

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title = "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.",

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doi = "10.1016/j.isci.2023.106442",

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AU - Coelho, Diego R.

AU - Palma, Flavio R.

AU - Paviani, Veronica

AU - LaFond, Katy M.

AU - Huang, Yunping

AU - Wang, Dongmei

AU - Wray, Brian

AU - Rao, Sridhar

AU - Yue, Feng

AU - Bonini, Marcelo G.

AU - Gantner, Benjamin N.

PY - 2023/4/21

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N2 - 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.

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

Abstract

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