دورية أكاديمية
Trem2 Agonist Reprograms Foamy Macrophages to Promote Atherosclerotic Plaque Stability-Brief Report.
العنوان: | Trem2 Agonist Reprograms Foamy Macrophages to Promote Atherosclerotic Plaque Stability-Brief Report. |
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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. |
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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 |
تدمد: | 1524-4636 |
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DOI: | 10.1161/ATVBAHA.124.320797 |