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Updated: May 19, 2026
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Published on: September 18, 2020
SOCS3 deficiency promotes M1 macrophage polarization and inflammation
Hongwei Qin1, Andrew T Holdbrooks, Yudong Liu
1Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA. hqin@uab.edu
Abstract:
Macrophages participate in both the amplification of inflammation at the time of injury and downregulation of the inflammatory response to avoid excess tissue damage. These divergent functions of macrophages are dictated by their microenvironment, especially cytokines, which promote a spectrum of macrophage phenotypes. The M1 proinflammatory phenotype is induced by LPS, IFN-γ, and GM-CSF, and IL-4, IL-13, and M-CSF induce anti-inflammatory M2 macrophages. Suppressors of cytokine signaling (SOCS) proteins function as feedback inhibitors of the JAK/STAT signaling pathway, and they can terminate innate and adaptive immune responses. In this study, we have evaluated the influence of SOCS3 on macrophage polarization and function. Macrophages obtained from LysMCre-SOCS3(fl/fl) mice, which lack SOCS3 in myeloid lineage cells, exhibit enhanced and prolonged activation of the JAK/STAT pathway compared with macrophages from SOCS3(fl/fl) mice. Furthermore, SOCS3-deficient macrophages have higher levels of the M1 genes IL-1β, IL-6, IL-12, IL-23, and inducible NO synthase owing to enhanced transcriptional activation and chromatin modifications. SOCS3-deficient M1 macrophages also have a stronger capacity to induce Th1 and Th17 cell differentiation than M1 macrophages from SOCS3(fl/fl) mice. Lastly, LPS-induced sepsis is exacerbated in LysMCre-SOCS3(fl/fl) mice and is associated with enhanced STAT1/3 activation and increased plasma levels of M1 cytokines/chemokines such as IL-1β, TNF-α, IL-6, CCL3, CCL4, and CXCL11. These findings collectively indicate that SOCS3 is involved in repressing the M1 proinflammatory phenotype, thereby deactivating inflammatory responses in macrophages.
Insights
Suppressors of cytokine signaling 3 (SOCS3) protein limits the M1 proinflammatory macrophage phenotype. Loss of SOCS3 in myeloid cells enhances M1 polarization and exacerbates sepsis, indicating SOCS3
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- Macrophages exhibit diverse phenotypes, including M1 (proinflammatory) and M2 (anti-inflammatory), influenced by cytokines.
- Suppressors of cytokine signaling (SOCS) proteins are key negative regulators of Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling.
- SOCS proteins are crucial for terminating innate and adaptive immune responses.
Purpose of the Study:
- To investigate the role of SOCS3 in regulating macrophage polarization and function.
- To determine the impact of SOCS3 deficiency on M1 macrophage activation and inflammatory responses.
Main Methods:
- Utilized LysMCre-SOCS3(fl/fl) mice lacking SOCS3 in myeloid lineage cells.
- Analyzed JAK/STAT pathway activation, M1 gene expression (IL-1β, IL-6, IL-12, IL-23, iNOS), and chromatin modifications.
- Assessed the capacity of SOCS3-deficient M1 macrophages to induce Th1 and Th17 cell differentiation.
- Evaluated the effect of SOCS3 deficiency on lipopolysaccharide (LPS)-induced sepsis severity.
Main Results:
- Macrophages lacking SOCS3 showed enhanced and prolonged JAK/STAT pathway activation.
- SOCS3-deficient macrophages exhibited increased M1 gene expression and chromatin modifications.
- SOCS3-deficient M1 macrophages displayed a heightened ability to induce Th1 and Th17 cell differentiation.
- LPS-induced sepsis was more severe in mice lacking SOCS3, with elevated M1 cytokine/chemokine levels.
Conclusions:
- SOCS3 plays a critical role in suppressing the M1 proinflammatory macrophage phenotype.
- SOCS3 acts as a negative regulator of inflammatory responses in macrophages.
- Targeting SOCS3 may offer therapeutic strategies for modulating inflammatory diseases.
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