دورية أكاديمية
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Trem2 Agonist Reprograms Foamy Macrophages to Promote Atherosclerotic Plaque Stability-Brief Report.

التفاصيل البيبلوغرافية
العنوان: Trem2 Agonist Reprograms Foamy Macrophages to Promote Atherosclerotic Plaque Stability-Brief Report.
المؤلفون: Patterson MT; Center for Immunology (M.T.P., Y.X., H.H., V.O., P.R.S., A.E.K., F.B., A.Z., S.T., S.S., I.M.S., X.S.R., B.A.B., J.W.W.), University of Minnesota, Minneapolis.; Department of Integrative Biology and Physiology (M.T.P., Y.X., H.H., P.R.S., A.E.K., F.B., A.Z., S.T., S.S., X.S.R., J.W.W.), University of Minnesota, Minneapolis., Xu Y; Center for Immunology (M.T.P., Y.X., H.H., V.O., P.R.S., A.E.K., F.B., A.Z., S.T., S.S., I.M.S., X.S.R., B.A.B., J.W.W.), University of Minnesota, Minneapolis.; Department of Integrative Biology and Physiology (M.T.P., Y.X., H.H., P.R.S., A.E.K., F.B., A.Z., S.T., S.S., X.S.R., J.W.W.), University of Minnesota, Minneapolis., Hillman H; Center for Immunology (M.T.P., Y.X., H.H., V.O., P.R.S., A.E.K., F.B., A.Z., S.T., S.S., I.M.S., X.S.R., B.A.B., J.W.W.), University of Minnesota, Minneapolis.; Department of Integrative Biology and Physiology (M.T.P., Y.X., H.H., P.R.S., A.E.K., F.B., A.Z., S.T., S.S., X.S.R., J.W.W.), University of Minnesota, Minneapolis., Osinski V; Center for Immunology (M.T.P., Y.X., H.H., V.O., P.R.S., A.E.K., F.B., A.Z., S.T., S.S., I.M.S., X.S.R., B.A.B., J.W.W.), University of Minnesota, Minneapolis.; Department of Pediatrics (V.O., B.A.B.), University of Minnesota, Minneapolis., Schrank PR; Center for Immunology (M.T.P., Y.X., H.H., V.O., P.R.S., A.E.K., F.B., A.Z., S.T., S.S., I.M.S., X.S.R., B.A.B., J.W.W.), University of Minnesota, Minneapolis.; Department of Integrative Biology and Physiology (M.T.P., Y.X., H.H., P.R.S., A.E.K., F.B., A.Z., S.T., S.S., X.S.R., J.W.W.), University of Minnesota, Minneapolis., Kennedy AE; Center for Immunology (M.T.P., Y.X., H.H., V.O., P.R.S., A.E.K., F.B., A.Z., S.T., S.S., I.M.S., X.S.R., B.A.B., J.W.W.), University of Minnesota, Minneapolis.; Department of Integrative Biology and Physiology (M.T.P., Y.X., H.H., P.R.S., A.E.K., F.B., A.Z., S.T., S.S., X.S.R., J.W.W.), University of Minnesota, Minneapolis., Barrow F; Center for Immunology (M.T.P., Y.X., H.H., V.O., P.R.S., A.E.K., F.B., A.Z., S.T., S.S., I.M.S., X.S.R., B.A.B., J.W.W.), University of Minnesota, Minneapolis.; Department of Integrative Biology and Physiology (M.T.P., Y.X., H.H., P.R.S., A.E.K., F.B., A.Z., S.T., S.S., X.S.R., J.W.W.), University of Minnesota, Minneapolis., Zhu A; Center for Immunology (M.T.P., Y.X., H.H., V.O., P.R.S., A.E.K., F.B., A.Z., S.T., S.S., I.M.S., X.S.R., B.A.B., J.W.W.), University of Minnesota, Minneapolis.; Department of Integrative Biology and Physiology (M.T.P., Y.X., H.H., P.R.S., A.E.K., F.B., A.Z., S.T., S.S., X.S.R., J.W.W.), University of Minnesota, Minneapolis., Tollison S; Center for Immunology (M.T.P., Y.X., H.H., V.O., P.R.S., A.E.K., F.B., A.Z., S.T., S.S., I.M.S., X.S.R., B.A.B., J.W.W.), University of Minnesota, Minneapolis.; Department of Integrative Biology and Physiology (M.T.P., Y.X., H.H., P.R.S., A.E.K., F.B., A.Z., S.T., S.S., X.S.R., J.W.W.), University of Minnesota, Minneapolis., Shekhar S; Center for Immunology (M.T.P., Y.X., H.H., V.O., P.R.S., A.E.K., F.B., A.Z., S.T., S.S., I.M.S., X.S.R., B.A.B., J.W.W.), University of Minnesota, Minneapolis.; Department of Integrative Biology and Physiology (M.T.P., Y.X., H.H., P.R.S., A.E.K., F.B., A.Z., S.T., S.S., X.S.R., J.W.W.), University of Minnesota, Minneapolis., Stromnes IM; Center for Immunology (M.T.P., Y.X., H.H., V.O., P.R.S., A.E.K., F.B., A.Z., S.T., S.S., I.M.S., X.S.R., B.A.B., J.W.W.), University of Minnesota, Minneapolis.; Department of Microbiology and Immunology (I.M.S.), University of Minnesota, Minneapolis., Tassi I; Alector, Inc, South San Francisco, CA (I.T., D.W.).; Now with Deep Apple Therapeutics, South San Francisco, CA (I.T.)., Wu D; Alector, Inc, South San Francisco, CA (I.T., D.W.)., Revelo XS; Center for Immunology (M.T.P., Y.X., H.H., V.O., P.R.S., A.E.K., F.B., A.Z., S.T., S.S., I.M.S., X.S.R., B.A.B., J.W.W.), University of Minnesota, Minneapolis.; Department of Integrative Biology and Physiology (M.T.P., Y.X., H.H., P.R.S., A.E.K., F.B., A.Z., S.T., S.S., X.S.R., J.W.W.), University of Minnesota, Minneapolis., Binstadt BA; Center for Immunology (M.T.P., Y.X., H.H., V.O., P.R.S., A.E.K., F.B., A.Z., S.T., S.S., I.M.S., X.S.R., B.A.B., J.W.W.), University of Minnesota, Minneapolis.; Department of Pediatrics (V.O., B.A.B.), University of Minnesota, Minneapolis., Williams JW; Center for Immunology (M.T.P., Y.X., H.H., V.O., P.R.S., A.E.K., F.B., A.Z., S.T., S.S., I.M.S., X.S.R., B.A.B., J.W.W.), University of Minnesota, Minneapolis.; Department of Integrative Biology and Physiology (M.T.P., Y.X., H.H., P.R.S., A.E.K., F.B., A.Z., S.T., S.S., X.S.R., J.W.W.), University of Minnesota, Minneapolis.
المصدر: Arteriosclerosis, thrombosis, and vascular biology [Arterioscler Thromb Vasc Biol] 2024 Jul; Vol. 44 (7), pp. 1646-1657. Date of Electronic Publication: 2024 May 02.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Lippincott Williams & Wilkins Country of Publication: United States NLM ID: 9505803 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1524-4636 (Electronic) Linking ISSN: 10795642 NLM ISO Abbreviation: Arterioscler Thromb Vasc Biol Subsets: MEDLINE
أسماء مطبوعة: Publication: 1998- : Baltimore, Md. : Lippincott Williams & Wilkins
Original Publication: Dallas, TX : American Heart Association, c1995-
مواضيع طبية MeSH: Plaque, Atherosclerotic* , Receptors, Immunologic*/agonists , Receptors, Immunologic*/metabolism , Receptors, Immunologic*/genetics , Membrane Glycoproteins*/agonists , Membrane Glycoproteins*/metabolism , Membrane Glycoproteins*/genetics , Disease Models, Animal* , Atherosclerosis*/pathology , Atherosclerosis*/metabolism , Atherosclerosis*/genetics , Atherosclerosis*/drug therapy , Atherosclerosis*/prevention & control , Foam Cells*/metabolism , Foam Cells*/pathology , Foam Cells*/drug effects , Mice, Inbred C57BL* , Mice, Knockout*, Animals ; Mice ; Male ; Receptors, LDL/genetics ; Receptors, LDL/metabolism ; Receptors, LDL/deficiency ; Cell Proliferation/drug effects ; Diet, High-Fat ; Cell Survival/drug effects ; Necrosis ; Aortic Diseases/pathology ; Aortic Diseases/genetics ; Aortic Diseases/metabolism ; Aortic Diseases/prevention & control
مستخلص: Background: Trem2 (triggering receptor on myeloid cells 2), a surface lipid receptor, is expressed on foamy macrophages within atherosclerotic lesions and regulates cell survival, proliferation, and anti-inflammatory responses. Studies examining the role of Trem2 in atherosclerosis have shown that deletion of Trem2 leads to impaired foamy macrophage lipid uptake, proliferation, survival, and cholesterol efflux. Thus, we tested the hypothesis that administration of a Trem2 agonist antibody (AL002a) to atherogenic mice would enhance macrophage survival and decrease necrotic core formation to improve plaque stability.
Methods: To model a therapeutic intervention approach, atherosclerosis-prone mice (Ldlr [low-density lipoprotein receptor] -/- ) were fed a high-fat diet for 8 weeks, then transitioned to treatment with AL002a or isotype control for an additional 8 weeks while continuing on a high-fat diet.
Results: AL002a-treated mice had increased lesion size in both the aortic root and whole mount aorta, which correlated with an expansion of plaque macrophage area. This expansion was due to increased macrophage survival and proliferation in plaques. Importantly, plaques from AL002a-treated mice showed improved features of plaque stability, including smaller necrotic cores, increased fibrous caps, and greater collagen deposition. Single-cell RNA sequencing of whole aorta suspensions from isotype- and AL002a-treated atherosclerotic mice revealed that Trem2 agonism dramatically altered foamy macrophage transcriptome. This included upregulation of oxidative phosphorylation and increased expression of collagen genes. In vitro studies validated that Trem2 agonism with AL002a promoted foamy macrophage oxidized low-density lipoprotein uptake, survival, and cholesterol efflux.
Conclusions: Trem2 agonism expands atherosclerotic plaque macrophages by promoting cell survival and proliferation but improves features of plaque stability by rewiring foamy macrophage function to enhance cholesterol efflux and collagen deposition.
Competing Interests: Disclosures D. Wu is an employee of Alector, Inc (South San Francisco, CA), and I. Tassi is an employee of Deep Apple Therapeutics (South San Francisco, CA). The other authors report no conflicts.
References: Arterioscler Thromb Vasc Biol. 2003 Dec;23(12):2123-30. (PMID: 14512372)
Circulation. 1995 Aug 1;92(3):657-71. (PMID: 7634481)
Arterioscler Thromb Vasc Biol. 2022 Jun;42(6):719-731. (PMID: 35477277)
Circ Res. 2021 Aug 20;129(5):530-546. (PMID: 34289717)
Cell. 2001 Feb 23;104(4):503-16. (PMID: 11239408)
Nat Rev Immunol. 2010 Jan;10(1):36-46. (PMID: 19960040)
Hypertension. 2002 Feb;39(2):258-63. (PMID: 11847194)
Neuron. 2020 Mar 4;105(5):837-854.e9. (PMID: 31902528)
Circ Res. 2020 Jul 17;127(3):402-426. (PMID: 32673538)
J Lipid Res. 2009 Apr;50 Suppl:S382-7. (PMID: 18953058)
Front Immunol. 2023 Jul 04;14:1215612. (PMID: 37469518)
Arterioscler Thromb Vasc Biol. 2017 Jul;37(7):e75-e81. (PMID: 28637702)
Arterioscler Thromb Vasc Biol. 2002 Sep 1;22(9):1370-80. (PMID: 12231554)
J Neuroinflammation. 2020 Aug 14;17(1):238. (PMID: 32795308)
Front Cell Neurosci. 2019 Oct 10;13:457. (PMID: 31649511)
J Exp Med. 2020 Sep 7;217(9):. (PMID: 32579671)
Circ Res. 2018 Oct 26;123(10):1127-1142. (PMID: 30359200)
Nat Immunol. 2019 Feb;20(2):163-172. (PMID: 30643263)
Eur J Immunol. 2011 Sep;41(9):2515-8. (PMID: 21952808)
Nat Cardiovasc Res. 2023 Nov;2(11):1015-1031. (PMID: 38646596)
J Immunol. 2006 Aug 15;177(4):2051-5. (PMID: 16887962)
Proc Natl Acad Sci U S A. 2002 May 28;99(11):7604-9. (PMID: 12032330)
Circ Res. 2014 Jun 6;114(12):1852-66. (PMID: 24902970)
Nat Methods. 2020 Feb;17(2):159-162. (PMID: 31819264)
Cardiovasc Res. 2000 Feb;45(3):736-46. (PMID: 10728396)
J Clin Invest. 2017 Feb 1;127(2):564-568. (PMID: 28067670)
Arterioscler Thromb Vasc Biol. 2005 Nov;25(11):2255-64. (PMID: 16141399)
Front Immunol. 2019 Jul 03;10:1462. (PMID: 31333642)
Cell. 2017 Aug 10;170(4):649-663.e13. (PMID: 28802038)
N Engl J Med. 1999 Jan 14;340(2):115-26. (PMID: 9887164)
Nature. 2016 Aug 4;536(7614):86-90. (PMID: 27437576)
Nat Med. 2019 Oct;25(10):1576-1588. (PMID: 31591603)
Arterioscler Thromb Vasc Biol. 2022 Nov;42(11):1283-1306. (PMID: 36134566)
Arterioscler Thromb Vasc Biol. 2020 Jan;40(1):20-33. (PMID: 31722535)
Proc Natl Acad Sci U S A. 2002 Sep 3;99(18):11896-901. (PMID: 12193651)
Nat Metab. 2021 Feb;3(2):166-181. (PMID: 33619382)
J Exp Med. 2022 Dec 5;219(12):. (PMID: 36107206)
N Engl J Med. 2021 Jan 28;384(4):382-383. (PMID: 33503349)
J Cell Sci. 2021 Sep 15;134(18):. (PMID: 34447991)
Immunity. 2023 Mar 14;56(3):516-530.e9. (PMID: 36738738)
Arterioscler Thromb Vasc Biol. 2017 Dec;37(12):2322-2332. (PMID: 28970293)
Nat Rev Mol Cell Biol. 2020 Jul;21(7):398-414. (PMID: 32251387)
معلومات مُعتمدة: R01 AI165553 United States AI NIAID NIH HHS; R01 HL166843 United States HL NHLBI NIH HHS
فهرسة مساهمة: Keywords: anti-inflammatory agents; cell proliferation; cholesterol; collagen; macrophages
المشرفين على المادة: 0 (Receptors, Immunologic)
0 (Trem2 protein, mouse)
0 (Membrane Glycoproteins)
0 (Receptors, LDL)
تواريخ الأحداث: Date Created: 20240502 Date Completed: 20240626 Latest Revision: 20240704
رمز التحديث: 20240704
مُعرف محوري في PubMed: PMC11208052
DOI: 10.1161/ATVBAHA.124.320797
PMID: 38695172
قاعدة البيانات: MEDLINE
الوصف
تدمد:1524-4636
DOI:10.1161/ATVBAHA.124.320797