دورية أكاديمية
أعرض في EDS

β2M Signals Monocytes Through Non-Canonical TGFβ Receptor Signal Transduction.

التفاصيل البيبلوغرافية
العنوان: β2M Signals Monocytes Through Non-Canonical TGFβ Receptor Signal Transduction.
المؤلفون: Hilt ZT; Aab Cardiovascular Research Institute (Z.T.H., P.M., L.T., D.N.P., S.K.T., C.N.M.), University of Rochester School of Medicine, NY.; Department of Microbiology and Immunology, Cornell University, Ithaca, NY (Z.T.H.)., Maurya P; Aab Cardiovascular Research Institute (Z.T.H., P.M., L.T., D.N.P., S.K.T., C.N.M.), University of Rochester School of Medicine, NY., Tesoro L; Aab Cardiovascular Research Institute (Z.T.H., P.M., L.T., D.N.P., S.K.T., C.N.M.), University of Rochester School of Medicine, NY.; Cardiology Department, University Francisco de Vitoria/Hospital Ramón y Cajal Research Unit (IRYCIS), CIBERCV, Madrid, Spain (L.T.)., Pariser DN; Aab Cardiovascular Research Institute (Z.T.H., P.M., L.T., D.N.P., S.K.T., C.N.M.), University of Rochester School of Medicine, NY., Ture SK; Aab Cardiovascular Research Institute (Z.T.H., P.M., L.T., D.N.P., S.K.T., C.N.M.), University of Rochester School of Medicine, NY., Cleary SJ; Department of Medicine, UCSF, San Francisco (S.J.C., M.R.L.)., Looney MR; Department of Medicine, UCSF, San Francisco (S.J.C., M.R.L.)., McGrath KE; Center for Pediatric Biomedical Research, Department of Pediatrics (K.E.M.), University of Rochester School of Medicine, NY., Morrell CN; Aab Cardiovascular Research Institute (Z.T.H., P.M., L.T., D.N.P., S.K.T., C.N.M.), University of Rochester School of Medicine, NY.; Departments of Medicine, Microbiology and Immunology and Pathology (C.N.M.).
المصدر: Circulation research [Circ Res] 2021 Mar 05; Vol. 128 (5), pp. 655-669. Date of Electronic Publication: 2021 Jan 29.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Lippincott Williams & Wilkins Country of Publication: United States NLM ID: 0047103 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1524-4571 (Electronic) Linking ISSN: 00097330 NLM ISO Abbreviation: Circ Res Subsets: MEDLINE
أسماء مطبوعة: Publication: Baltimore, MD : Lippincott Williams & Wilkins
Original Publication: Baltimore, Md. Grune & Stratton.
مواضيع طبية MeSH: Signal Transduction*, Monocytes/*metabolism , Receptors, Transforming Growth Factor beta/*metabolism , beta 2-Microglobulin/*metabolism, Animals ; Cell Differentiation ; Cells, Cultured ; Humans ; MAP Kinase Kinase 4/metabolism ; Mice ; Mice, Inbred C57BL ; Monocytes/cytology ; Monocytes/drug effects ; NF-kappa B/metabolism ; Smad Proteins/metabolism ; THP-1 Cells ; beta 2-Microglobulin/pharmacology
مستخلص: Rationale: Circulating 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.
Objective: To 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 Results: Wild-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.
Conclusions: Our 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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معلومات مُعتمدة: R21 HL153409 United States HL NHLBI NIH HHS; R01 HL141106 United States HL NHLBI NIH HHS; UL1 TR002001 United States TR NCATS NIH HHS; R01 HL142152 United States HL NHLBI NIH HHS; R01 HL138673 United States HL NHLBI NIH HHS
فهرسة مساهمة: Keywords: cytokines; inflammation; monocytes; platelets; transforming growth factors
المشرفين على المادة: 0 (NF-kappa B)
0 (Receptors, Transforming Growth Factor beta)
0 (Smad Proteins)
0 (beta 2-Microglobulin)
EC 2.7.12.2 (MAP Kinase Kinase 4)
تواريخ الأحداث: Date Created: 20210129 Date Completed: 20211001 Latest Revision: 20231019
رمز التحديث: 20231019
مُعرف محوري في PubMed: PMC8319031
DOI: 10.1161/CIRCRESAHA.120.317119
PMID: 33508948
قاعدة البيانات: MEDLINE
الوصف
تدمد:1524-4571
DOI:10.1161/CIRCRESAHA.120.317119