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ILC2 transfers to apolipoprotein E deficient mice reduce the lipid content of atherosclerotic lesions.

ABSTRACT: BACKGROUND:Expansion of type 2 innate lymphoid cells (ILC2s) in hypercholesterolaemic mice protects against atherosclerosis while different ILC2 subsets have been described (natural, inflammatory) based on their suppression of tumorigenicity 2 (ST2) and killer-cell lectin like receptor G1 (KLRG1) expression. The aim of the current study is to characterize the interleukin 25 (IL25)-induced splenic ILC2 population (Lin-CD45+IL17RB+ICOS+IL7raintermediate) and address its direct role in experimental atherosclerosis by its adoptive transfer to hypercholesterolaemic apolipoprotein E deficient (apoE-/-) mice. RESULTS:Immunomagnetically enriched, FACS-sorted ILC2s from the spleens of IL-25 treated apoE-/- mice were stained for KLRG1 and ST2 directly upon cell obtainment or in vitro cell expansion for flow cytometric analysis. IL25-induced splenic ILC2s express high levels of both KLRG1 and ST2. However, both markers are downregulated upon in vitro cell expansion. In vitro expanded splenic ILC2s were intraperitoneally transferred to apoE-/- recipients on high fat diet. ApoE-/- mice that received in vitro expanded splenic ILC2s had decreased lipid content in subvalvular heart and brachiocephalic artery (BCA) plaques accompanied by increased peritoneal B1 cells, activated eosinophils and alternatively activated macrophages (AAMs) as well as anti-phosphorylcholine (PC) immunoglobulin (Ig) M in plasma. CONCLUSIONS:With the current data we designate the IL25-induced ILC2 population to decrease the lipid content of atherosclerotic lesions in apoE-/- mice and we directly link the induction of B1 cells and the atheroprotective anti-PC IgM antibodies with ILC2s.

SUBMITTER: Mantani PT

PROVIDER: S-EPMC6905041 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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ILC2 transfers to apolipoprotein E deficient mice reduce the lipid content of atherosclerotic lesions.

Mantani Polyxeni T PT Dunér Pontus P Ljungcrantz Irena I Nilsson Jan J Björkbacka Harry H Fredrikson Gunilla Nordin GN

BMC immunology 20191210 1

<h4>Background</h4>Expansion of type 2 innate lymphoid cells (ILC2s) in hypercholesterolaemic mice protects against atherosclerosis while different ILC2 subsets have been described (natural, inflammatory) based on their suppression of tumorigenicity 2 (ST2) and killer-cell lectin like receptor G1 (KLRG1) expression. The aim of the current study is to characterize the interleukin 25 (IL25)-induced splenic ILC2 population (Lin<sup>-</sup>CD45<sup>+</sup>IL17RB<sup>+</sup>ICOS<sup>+</sup>IL7ra<sup> ...[more]

PMID: 31823769

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Project description:Aims/hypothesisSeveral lines of evidence suggest that incretin-based therapies suppress the development of cardiovascular disease in type 2 diabetes. We investigated the possibility that glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) can prevent the development of atherosclerosis in Apoe (-/-) mice.MethodsApoe (-/-) mice (17 weeks old) were administered GLP-1(7-36)amide, GLP-1(9-36)amide, GIP(1-42) or GIP(3-42) for 4 weeks. Aortic atherosclerosis, oxidised LDL-induced foam cell formation and related gene expression in exudate peritoneal macrophages were determined.ResultsAdministration of GLP-1(7-36)amide or GIP(1-42) significantly suppressed atherosclerotic lesions and macrophage infiltration in the aortic wall, compared with vehicle controls. These effects were cancelled by co-infusion with specific antagonists for GLP-1 and GIP receptors, namely exendin(9-39) or Pro(3)(GIP). The anti-atherosclerotic effects of GLP-1(7-36)amide and GIP(1-42) were associated with significant decreases in foam cell formation and downregulation of CD36 and acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT-1) in macrophages. GLP-1 and GIP receptors were both detected in Apoe (-/-) mouse macrophages. Ex vivo incubation of macrophages with GLP-1(7-36)amide or GIP(1-42) for 48 h significantly suppressed foam cell formation. This effect was wholly abolished in macrophages pretreated with exendin(9-39) or (Pro(3))GIP, or with an adenylate cyclase inhibitor, MDL12,330A, and was mimicked by incubation with an adenylate cyclase activator, forskolin. The inactive forms, GLP-1(9-36)amide and GIP(3-42), had no effects on atherosclerosis and macrophage foam cell formation.Conclusions/interpretationOur study is the first to demonstrate that active forms of GLP-1 and GIP exert anti-atherogenic effects by suppressing macrophage foam cell formation via their own receptors, followed by cAMP activation. Molecular mechanisms underlying these effects are associated with the downregulation of CD36 and ACAT-1 by incretins.

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ILC2 transfers to apolipoprotein E deficient mice reduce the lipid content of atherosclerotic lesions.

Publications

ILC2 transfers to apolipoprotein E deficient mice reduce the lipid content of atherosclerotic lesions.

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