دورية أكاديمية
β2M Signals Monocytes Through Non-Canonical TGFβ Receptor Signal Transduction.
العنوان: | β2M Signals Monocytes Through Non-Canonical TGFβ Receptor Signal Transduction. |
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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. |
References: | Science. 2015 Nov 20;350(6263):985-90. (PMID: 26494174) PLoS One. 2017 Nov 20;12(11):e0188317. (PMID: 29155869) Annu Rev Immunol. 2008;26:421-52. (PMID: 18303997) Trends Immunol. 2003 May;24(5):228-9; author reply 229-30. (PMID: 12738410) Proc Natl Acad Sci U S A. 2014 Nov 25;111(47):16736-41. (PMID: 25385595) Immunity. 2003 Jul;19(1):71-82. (PMID: 12871640) Cancer Sci. 2008 Nov;99(11):2107-12. (PMID: 18808420) Nat Med. 1995 Sep;1(9):932-7. (PMID: 7585220) Cells. 2014 Oct 15;3(4):981-93. (PMID: 25317929) J Immunol. 2002 Sep 1;169(5):2611-8. (PMID: 12193732) Blood. 2011 Aug 4;118(5):e16-31. (PMID: 21653326) Ups J Med Sci. 2012 May;117(2):153-65. (PMID: 22335355) PLoS Comput Biol. 2014 May 08;10(5):e1003606. (PMID: 24809460) EMBO J. 1998 Feb 16;17(4):996-1005. (PMID: 9463378) Mol Biol Cell. 2001 May;12(5):1431-43. (PMID: 11359933) Science. 2013 Jan 11;339(6116):218-22. (PMID: 23223452) J Biol Chem. 2016 Feb 26;291(9):4626-37. (PMID: 26655720) Nature. 2011 Jun 15;474(7351):343-9. (PMID: 21677751) Cell. 2009 Jan 9;136(1):123-35. (PMID: 19135894) Mol Cell Biol. 1997 May;17(5):2521-8. (PMID: 9111321) Oncotarget. 2016 Aug 9;7(32):52294-52306. (PMID: 27418133) Nat Immunol. 2009 Nov;10(11):1200-7. (PMID: 19801985) J Biol Chem. 2000 Nov 24;275(47):36818-22. (PMID: 11016919) J Leukoc Biol. 2008 May;83(5):1165-73. (PMID: 18252868) Am J Cardiol. 2015 Oct 1;116(7):1034-40. (PMID: 26254706) Biochem J. 2013 May 1;451(3):375-88. (PMID: 23421427) Anticancer Agents Med Chem. 2014 Mar;14(3):343-52. (PMID: 23848204) Immunity. 2010 Sep 24;33(3):375-86. (PMID: 20832340) Methods Mol Biol. 2016;1344:355-63. (PMID: 26520137) Oncogene. 2013 Mar 21;32(12):1549-59. (PMID: 22641218) Circ Res. 2014 May 9;114(10):1611-22. (PMID: 24625784) Mol Cell. 2008 Sep 26;31(6):918-24. (PMID: 18922473) Int J Mol Sci. 2017 Jan 19;18(1):. (PMID: 28106845) Cell Tissue Res. 2012 Jan;347(1):11-20. (PMID: 21701805) Aging (Albany NY). 2019 Dec 18;11(24):11955-11974. (PMID: 31852838) J Immunol. 2000 Jun 15;164(12):6166-73. (PMID: 10843666) JCI Insight. 2019 Mar 7;4(5):. (PMID: 30702442) Biomark Res. 2014 Jan 07;2(1):1. (PMID: 24398220) Chin Med J (Engl). 2016 Feb 20;129(4):448-55. (PMID: 26879019) |
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 |
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