S100A9 blockade ameliorates cardiac dysfunction and reduces myocardial immune infiltration in experimental autoimmune myocarditis. (10th June 2022)

• Record Type: Journal Article
• Authors: Jakobsson, G; Mulholland, M; Grentzmann, A; Ljungcrantz, I; Rattik, S; Engelbertsen, D; Schiopu, A
• Is Part Of: Cardiovascular research. Volume 118(2022)Supplement 1
• Publication Date: 2022-06-10
• Subjects: Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Periodicals; 616.1
• DOI: 10.1093/cvr/cvac066.147
• Languages: English
• ISSNs: 0008-6363

Abstract

Abstract: Funding Acknowledgements: Type of funding sources: Public Institution(s). Main funding source(s): Swedish Heart and Lung Foundation and Swedish Research Council Background/Introduction: Autoimmune myocarditis is characterized by non-ischemic inflammatory heart injury, leading to myocardial damage and impaired cardiac function. S100A9 is an inflammatory alarmin present in large amounts in neutrophils. The role of S100A9 as a potential treatment target in myocarditis has not been fully explored. Aim: We sought to investigate the impact of S100A9 blockade in experimental autoimmune myocarditis and assess the effects of treatment on cardiac function and immune infiltration. Methods: BALB/C mice were immunized with αMHC peptide emulsified in Complete Freunds Adjuvant at day 0 and day 7 to induce the disease. The water-soluble small-molecule S100A9 blocker ABR-238901 was given continuously in drinking water starting on day 7. Echocardiography was performed weekly from day 21 to day 42 (n=11/group). For flow cytometry analysis, mice were sacrificed at day 21 (n=10/group). Results: S100A9 blockade improved left ventricular ejection fraction [52.33% vs 44.87% on day 42 (p<0.001)]. Cardiac output was significantly improved on day 21 (12.69 vs 11.05 mL/min, p<0.05). We found a significant reduction of inflammatory cardiac infiltrates at day 21, characterized by reduced number of macrophages (p<0.05), neutrophils (p<0.01) and CD4+ T cells (p<0.05). The cardiac draining lymph nodes contained fewer dendritic cells (p<0.01), T cells (p<0.05), as well as reduced numbers of inflammatory CD4+ cells producing IL-17 (p<0.05). Conclusion: Therapeutic S100A9 blockade inhibits inflammatory cardiac infiltration and improves cardiac function in experimental autoimmune myocarditis. Our findings highlight the important role of S100A9 in the pathogenesis of myocarditis and identify S100A9 blockade as a possible novel therapeutic avenue.