**1. Introduction**

Myocarditis is a major cause of heart failure in young adults. Infections with cardiotropic viruses represent the most common etiology of myocarditis in the Western World. Release of cardiac self-antigens can subsequently lead to breakdown of heart-specific tolerance tissue and can evolve into autoimmune-mediated inflammation sustaining the disease upon eradication of the virus. Sustained cardiac inflammation may eventually lead to cardiac remodeling and end-stage heart failure with dilation of the ventricles and deteriorating contractility of the cardiac muscle, a condition called inflammatory dilated cardiomyopathy (DCMi) [1]. We recently showed that neutrophils play a critical role for cardiac inflammation in the experimental autoimmune myocarditis (EAM) mouse model which resembles the immunological and histopathological features of post-viral heart disease [2,3]. In this model, cardiac inflammation was induced by administration of a cardiac peptide together

with complete Freund's adjuvant which triggered an autoimmune response with a peak of leukocyte infiltration at day 21 after immunization. We demonstrated that targeting neutrophil extracellular traps (NETs), a process by which neutrophils expel their nuclear DNA together with antibacterial proteins, thereby maintaining tissue inflammation, can substantially reduce cardiac inflammation in the EAM mouse model [2,4]. In order to undergo NET formation in the inflamed cardiac tissue, neutrophils must be recruited from the blood stream into the tissue by crossing the endothelial barrier of the cardiac vasculature. The neutrophil recruitment cascade consists of consecutive events including capturing of free-flowing neutrophils, rolling, adhesion, adhesion strengthening, intraluminal crawling, and transmigration [5]. The lymphocyte function-associated antigen 1 (LFA-1, CD11a/CD18) and the macrophage 1-antigen (Mac-1, CD11b/CD18), adhesion molecules of the beta2-integrin family, are of fundamental importance for neutrophil adhesion and subsequent recruitment into the inflamed tissue [6]. LFA-1 also acts as an important adhesion molecule for other leukocyte subsets during the recruitment process, e.g., for T cells. Beyond its role for leukocyte recruitment, the interaction of LFA-1 on T cells with its ligand (the intercellular molecule-1 (ICAM-1)) on antigen-presenting cells like dendritic cells can provide a co-stimulatory signal for T cell activation. It has been shown that LFA-1 signaling influences differentiation of T cells into specific effector subsets. Engagement of LFA-1 on T cells can activate the Notch pathway promoting Th1 differentiation and suppressing generation of Th17 cells and regulatory T cells [7]. LFA-1 has been investigated as target in different autoimmune diseases. In psoriasis, an antibody targeting LFA-1 resulted in significant improvement of plaque psoriasis in patients with moderate to severe disease [8]. In contrast, in the experimental autoimmune encephalomyelitis (EAE) model, infiltration of leukocytes into the spinal cord and the brain was substantially enhanced in LFA-1-/- mice which was accompanied by increased disease severity suggesting that LFA-1 was protective in this model [9]. The role of LFA-1 in myocarditis is unclear. In this study, we set out to investigate the role of LFA-1 in myocarditis using the EAM model.
