ArticleJournal of immunology (Baltimore, Md. : 1950)2021
Non-Lyn Src Family Kinases Activate SIRPα-SHP-1 to Inhibit PI3K-Akt2 and Dampen Proinflammatory Macrophage Polarization.
Article in Journal of immunology (Baltimore, Md. : 1950), 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 25 citations in OpenAlex.
- Biallelic loss-of-function PTPN6 variants lead to inflammatory lung disease and hemolytic anemia.The Journal of experimental medicine · 2026Article
- A pan-cancer landscape of LILRB4 identifies it as a context-dependent marker of the myeloid and antigen-presentation axis.Translational oncology · 2026Article
- Progress in immunological research on innate effectors in xenotransplantation.Surgery today · 2026Review
- Post-translational modifications of immune checkpoints: molecular mechanisms, tumor microenvironment remodeling, and therapeutic implications.Journal of biomedical science · 2026Review
- Multi-omics integration and experimental validation reveal the mechanism of berberine against triple-negative breast cancer.Frontiers in pharmacology · 2026Article
- Bacterial EPIYA/EPIYA-like effector motifs and host regulatory pY-SH2 logic: a sequence-informed three-layer convergence model.Frontiers in cellular and infection microbiology · 2026Article
- Targeting the CD47-SIRPα Axis in Atherosclerosis: From Pathogenesis to Therapeutic Implications.Journal of inflammation research · 2026Review
- Article
- Phosphatases in tumor cell immune escape: a perspective based on the camouflage, coercion, cytoprotection.Frontiers in cell and developmental biology · 2026Review
- The SIRP family: from structural diversity and signaling mechanisms to implications in immune-related disease targeted therapeutics.Frontiers in immunology · 2026Review
- Targeting SHP-1 to alleviate testicular inflammation and apoptosis in a Poly(I:C)-induced orchitis model.European journal of medical research · 2025Article
- CD47/SIRPα pathways: Functional diversity and molecular mechanisms.World journal of biological chemistry · 2025Review
- Tumor-associated macrophages (TAMs): Constructing an immunosuppressive microenvironment bridge for pancreatic ductal adenocarcinoma (PDAC).Cancer pathogenesis and therapy · 2025Review
- Positive feedback loop involving AMPK and CLYBL acetylation links metabolic rewiring and inflammatory responses.Cell death & disease · 2025Article
- Adaptive immune cells antagonize ILC2 homeostasis via SLAMF3 and SLAMF5.Science advances · 2025Article
- Decoding CD24: Roles of chemoradiotherapy resistance and potential as therapeutic targets.Oncology research · 2025Review
- Non-Coding RNA in Tumor Cells and Tumor-Associated Myeloid Cells-Function and Therapeutic Potential.International journal of molecular sciences · 2024Review
- Hypercholesterolemia exacerbates in-stent restenosis in rabbits: Studies of the mitigating effect of stent surface modification with a CD47-derived peptide.Atherosclerosis · 2024Article
- Surfactant protein D prevents mucin overproduction in airway goblet cells via SIRPα.Scientific reports · 2024Article
- Counteracting Immunosenescence-Which Therapeutic Strategies Are Promising?Biomolecules · 2023Review
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Macrophage functional plasticity plays a central role in responding to proinflammatory stimuli. The molecular basis underlying the dynamic phenotypic activation of macrophages, however, remains incompletely understood. In this article, we report that SIRPα is a chief negative regulator of proinflammatory macrophage polarization. In response to TLR agonists, proinflammatory cytokines, or canonical M1 stimulation, Src family kinases (SFK) excluding Lyn phosphorylate SIRPα ITIMs, leading to the preferential recruitment and activation of SHP-1, but not SHP-2. Solely extracellular ligation of SIRPα by CD47 does not greatly induce phosphorylation of SIRPα ITIMs, but it enhances proinflammatory stimuli-induced SIRPα phosphorylation. Examination of downstream signaling elicited by IFN-γ and TLR3/4/9 agonists found that SIRPα-activated SHP-1 moderately represses STAT1, NF-κB, and MAPK signaling but markedly inhibits Akt2, resulting in dampened proinflammatory cytokine production and expression of Ag presentation machinery. Pharmacological inhibition of SHP-1 or deficiency of SIRPα conversely attenuates SIRPα-mediated inhibition and, as such, augments macrophage proinflammatory polarization that in turn exacerbates proinflammation in mouse models of type I diabetes and peritonitis. Our results reveal an SFK-SIRPα-SHP-1 mechanism that fine-tunes macrophage proinflammatory phenotypic activation via inhibition of PI3K-Akt2, which controls the transcription and translation of proinflammatory cytokines, Ag presentation machinery, and other cellular programs.
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