Dimitrios Tsiantoulas1, Ilze Bot1, Maria Ozsvar-Kozma1, Laura Göderle1, Thomas Perkmann1, Karsten Hartvigsen1, Daniel H Conrad1, Johan Kuiper1, Ziad Mallat1, Christoph J Binder2. 1. From the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria (D.T., M.O.-K., L.G., K.H., C.J.B.); Department of Laboratory Medicine, Medical University of Vienna, Austria (D.T., M.O.-K., L.G., T.P., K.H., C.J.B.); Division of Biopharmaceutics, LACDR Leiden University, The Netherlands (I.B., J.K.); Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond (D.H.C.); and Division of Cardiovascular Medicine, University of Cambridge, United Kingdom (Z.M.). 2. From the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria (D.T., M.O.-K., L.G., K.H., C.J.B.); Department of Laboratory Medicine, Medical University of Vienna, Austria (D.T., M.O.-K., L.G., T.P., K.H., C.J.B.); Division of Biopharmaceutics, LACDR Leiden University, The Netherlands (I.B., J.K.); Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond (D.H.C.); and Division of Cardiovascular Medicine, University of Cambridge, United Kingdom (Z.M.). christoph.binder@meduniwien.ac.at dimitris.tsiantoulas@meduniwien.ac.at.
Abstract
RATIONALE: Deficiency of secreted IgM (sIgM-/-) accelerates atherosclerosis in Ldlr-/-mice. Several atheroprotective effects of increased levels of IgM antibodies have been suggested, including preventing inflammation induced by oxidized low-density lipoprotein and promoting apoptotic cell clearance. However, the mechanisms by which the lack of sIgM promotes lesion formation remain unknown. OBJECTIVE: To identify the mechanisms by which sIgM deficiency accelerates atherosclerosis in mice. METHODS AND RESULTS: We here show that both sIgM-/- and Ldlr-/-sIgM-/- mice develop increased plasma IgE titers because of impaired generation of B cells expressing the low-affinity IgE receptor CD23, which mediates the clearance of IgE antibodies. We further report that Ldlr-/-sIgM-/- mice exhibit increased numbers of activated mast cells and neutrophils in the perivascular area of atherosclerotic plaques. Treatment with an anti-IgE-neutralizing antibody fully reversed vascular inflammation and accelerated atherosclerotic lesion formation in cholesterol-fed Ldlr-/-sIgM-/- mice. CONCLUSIONS: Thus, our data identify a previously unsuspected mechanism by which sIgM deficiency aggravates atherosclerosis.
RATIONALE: Deficiency of secreted IgM (sIgM-/-) accelerates atherosclerosis in Ldlr-/-mice. Several atheroprotective effects of increased levels of IgM antibodies have been suggested, including preventing inflammation induced by oxidized low-density lipoprotein and promoting apoptotic cell clearance. However, the mechanisms by which the lack of sIgM promotes lesion formation remain unknown. OBJECTIVE: To identify the mechanisms by which sIgM deficiency accelerates atherosclerosis in mice. METHODS AND RESULTS: We here show that both sIgM-/- and Ldlr-/-sIgM-/- mice develop increased plasma IgE titers because of impaired generation of B cells expressing the low-affinity IgE receptor CD23, which mediates the clearance of IgE antibodies. We further report that Ldlr-/-sIgM-/- mice exhibit increased numbers of activated mast cells and neutrophils in the perivascular area of atherosclerotic plaques. Treatment with an anti-IgE-neutralizing antibody fully reversed vascular inflammation and accelerated atherosclerotic lesion formation in cholesterol-fed Ldlr-/-sIgM-/- mice. CONCLUSIONS: Thus, our data identify a previously unsuspected mechanism by which sIgM deficiency aggravates atherosclerosis.
Authors: Mark A Hutchinson; Han-Sol Park; Kimberly J Zanotti; Juan Alvarez-Gonzalez; Jing Zhang; Li Zhang; Richard Telljohann; Mingyi Wang; Edward G Lakatta; Patricia J Gearhart; Robert W Maul Journal: Front Immunol Date: 2021-07-09 Impact factor: 7.561