ArticleCirculation research2021
β2M Signals Monocytes Through Non-Canonical TGFβ Receptor Signal Transduction.
Article in Circulation research, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers, 1 of them a synthesis that pooled it.
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Who cites it
16 citing papers in PubMed, 1 synthesis or guideline pooled it, 25 citations in OpenAlex.
- Causal relationship between beta-2 microglobulin and B-cell malignancies: genome-wide meta-analysis and a bidirectional two-sample Mendelian randomization study.Frontiers in immunology · 2024Pooled it
- Neonatal platelets differentiate monocytes to a myeloid-derived suppressor cell phenotype.Blood · 2026Article
- Cross-species comparison of platelet proteomes reveals developmentally regulated metabolic and inflammatory changes.Blood vessels, thrombosis & hemostasis · 2026Article
- Monocytes Defined by Platelet Interactions and Oxidative Stress Signaling Underlie HIV-Associated Atherosclerosis.Journal of the American Heart Association · 2026Article
- Macrophages in tumors with downregulated MHC-I expression: emerging therapeutic opportunities and translational challenges.Clinical and experimental immunology · 2026Review
- A platelet transcriptomic signature of thromboinflammation predicts cardiovascular risk.JCI insight · 2025Article
- Radiation regulates the expression of HLA-I in esophageal squamous cell carcinoma through interferon-γ.Scientific reports · 2025Article
- [Epithelial-mesenchymal Transition: Biological Basis and Clinical Prospects of Lung Cancer Invasion, Metastasis, and Drug Resistance].Zhongguo fei ai za zhi = Chinese journal of lung cancer · 2025Review
- Computational analysis of phytocompounds inHeliyon · 2024Article
- TGFβ signaling pathway is altered by HLA-B27 expression, resulting in pathogenic consequences relevant for spondyloarthritis.Arthritis research & therapy · 2024Article
- Plasma Proteomics Identifies B2M as a Regulator of Pulmonary Hypertension in Heart Failure With Preserved Ejection Fraction.Arteriosclerosis, thrombosis, and vascular biology · 2024Article
- Thrombocytopenia Independently Leads to Changes in Monocyte Immune Function.Circulation research · 2024Article
- Transfusion of Adult, but Not Neonatal, Platelets Promotes Monocyte Trafficking in Neonatal Mice.Arteriosclerosis, thrombosis, and vascular biology · 2023Article
- Platelet-monocyte aggregates: molecular mediators of thromboinflammation.Frontiers in cardiovascular medicine · 2023Review
- Article
- The Fra-1: Novel role in regulating extensive immune cell states and affecting inflammatory diseases.Frontiers in immunology · 2022Review
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Authors and funding
9 authors at 5 institutions in 3 countries.
Funding
Abstract
rationaleCirculating monocytes can have proinflammatory or proreparative phenotypes. The endogenous signaling molecules and pathways that regulate monocyte polarization in vivo are poorly understood. We have shown that platelet-derived β2M (β-2 microglobulin) and TGF-β (transforming growth factor β) have opposing effects on monocytes by inducing inflammatory and reparative phenotypes, respectively, but each bind and signal through the same receptor. We now define the signaling pathways involved.
objectiveTo determine the molecular mechanisms and signal transduction pathways by which β2M and TGF-β regulate monocyte responses both in vitro and in vivo. METHODS AND
resultsWild-type- (WT) and platelet-specific β2M knockout mice were treated intravenously with either β2M or TGF-β to increase plasma concentrations to those in cardiovascular diseases. Elevated plasma β2M increased proinflammatory monocytes, while increased plasma TGFβ increased proreparative monocytes. TGF-βR (TGF-β receptor) inhibition blunted monocyte responses to both β2M and TGF-β in vivo. Using imaging flow cytometry, we found that β2M decreased monocyte SMAD2/3 nuclear localization, while TGF-β promoted SMAD nuclear translocation but decreased noncanonical/inflammatory (JNK [jun kinase] and NF-κB [nuclear factor-κB] nuclear localization). This was confirmed in vitro using both imaging flow cytometry and immunoblots. β2M, but not TGF-β, promoted ubiquitination of SMAD3 and SMAD4, that inhibited their nuclear trafficking. Inhibition of ubiquitin ligase activity blocked noncanonical SMAD-independent monocyte signaling and skewed monocytes towards a proreparative monocyte response.
conclusionsOur findings indicate that elevated plasma β2M and TGF-β dichotomously polarize monocytes. Furthermore, these immune molecules share a common receptor but induce SMAD-dependent canonical signaling (TGF-β) versus noncanonical SMAD-independent signaling (β2M) in a ubiquitin ligase dependent manner. This work has broad implications as β2M is increased in several inflammatory conditions, while TGF-β is increased in fibrotic diseases. Graphic Abstract: A graphic abstract is available for this article.
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