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SHR Neuro Cancer Cardio Lipid Metab Microb

Forte, E; Perkins, B; Sintou, A; Kalkat, HS; Papanikolaou, A; Jenkins, C; Alsubaie, M; Chowdhury, RA; Duffy, TM; Skelly, DA; Branca, J; Bellahcene, M; Schneider, MD; Harding, SE; Furtado, MB; Ng, FS; Hasham, MG; Rosenthal, N; Sattler, S.
Cross-Priming Dendritic Cells Exacerbate Immunopathology After Ischemic Tissue Damage in the Heart.
Circulation. 2021; 143(8): 821-836. Doi: 10.1161/CIRCULATIONAHA.120.044581 [OPEN ACCESS]
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Leading authors Med Uni Graz

Sattler Susanne

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Abstract:

BACKGROUND: Ischemic heart disease is a leading cause of heart failure and despite advanced therapeutic options, morbidity and mortality rates remain high. Although acute inflammation in response to myocardial cell death has been extensively studied, subsequent adaptive immune activity and anti-heart autoimmunity may also contribute to the development of heart failure. After ischemic injury to the myocardium, dendritic cells (DC) respond to cardiomyocyte necrosis, present cardiac antigen to T cells, and potentially initiate a persistent autoimmune response against the heart. Cross-priming DC have the ability to activate both CD4⁺ helper and CD8⁺ cytotoxic T cells in response to necrotic cells and may thus be crucial players in exacerbating autoimmunity targeting the heart. This study investigates a role for cross-priming DC in post-myocardial infarction immunopathology through presentation of self-antigen from necrotic cardiac cells to cytotoxic CD8⁺ T cells. METHODS: We induced type 2 myocardial infarction-like ischemic injury in the heart by treatment with a single high dose of the β-adrenergic agonist isoproterenol. We characterized the DC population in the heart and mediastinal lymph nodes and analyzed long-term cardiac immunopathology and functional decline in wild type and Clec9a-depleted mice lacking DC cross-priming function. RESULTS: A diverse DC population, including cross-priming DC, is present in the heart and activated after ischemic injury. Clec9a^-/- mice deficient in DC cross-priming are protected from persistent immune-mediated myocardial damage and decline of cardiac function, likely because of dampened activation of cytotoxic CD8⁺ T cells. CONCLUSION: Activation of cytotoxic CD8⁺ T cells by cross-priming DC contributes to exacerbation of postischemic inflammatory damage of the myocardium and corresponding decline in cardiac function. Importantly, this provides novel therapeutic targets to prevent postischemic immunopathology and heart failure.

Find related publications in this database (using NLM MeSH Indexing)

Animals - administration & dosage

Antigen Presentation - administration & dosage

CD8-Positive T-Lymphocytes - immunology, metabolism

Cross-Priming - administration & dosage

Dendritic Cells - immunology, metabolism

Disease Models, Animal - administration & dosage

Female - administration & dosage

Heart Failure - pathology

Humans - administration & dosage

Lectins, C-Type - deficiency, genetics

Lymph Nodes - immunology, metabolism

Male - administration & dosage

Mice - administration & dosage

Mice, Inbred C57BL - administration & dosage

Mice, Knockout - administration & dosage

Middle Aged - administration & dosage

Myocardial Infarction - immunology, metabolism, pathology

Myocardium - immunology, metabolism, pathology

Receptors, Chemokine - metabolism

Receptors, Immunologic - deficiency, genetics

Find related publications in this database (Keywords)

autoimmunity

dendritic cells

heart failure

myocardial infarction

myocardial ischemia

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