Pharmacological MALT1 inhibition ameliorates cardiac inflammation and dysfunction in experimental autoimmune myocarditis
A Remes, R M Ignaz, V A Zirkenbach, M Noormalal, L Andresen, R Oettl, S S Hille, Z Cehreli, M Kaya, D Frank, N Frey, O J Mueller, Z KayaAbstract
Background
Autoimmune myocarditis is an inflammatory disease of the heart muscle driven by an aberrant immune response against cardiac antigens, characterized by pathogenic activation of autoreactive T cells and autoantibody production, ultimately leading to myocardial injury and cardiac dysfunction. Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is a key regulator of adaptive immune responses, acting downstream of the CARD11-BCL10-MALT1 complex to promote NF-κB–dependent T cell activation and pro-inflammatory cytokine production. Dysregulated MALT1 signaling has been implicated in multiple autoimmune diseases, yet its role in autoimmune myocarditis remains poorly defined.
Purpose
Given the central role of MALT1 in autoimmune pathogenesis and pro-inflammatory signal amplification, we investigated whether selective MALT1 inhibition attenuates disease progression in a murine model of experimental autoimmune myocarditis (EAM).
Methods
Experimental autoimmune myocarditis was induced in susceptible A/J mice by immunization with cardiac troponin I (cTnI) peptide. Mice received daily treatment with a selective MALT1 inhibitor (MI-2). Cardiac function was assessed by echocardiography. Serum anti-cTnI autoantibody levels were quantified by ELISA. Cardiac gene expression of hypertrophy, inflammation and fibrosis-related markers was analyzed by quantitative real-time PCR. Cardiomyocyte apoptosis was assessed by TUNEL assay, and extracellular matrix deposition was evaluated by AFOG staining.
Results
MI-2 treatment significantly attenuated myocardial injury and improved cardiac function in the EAM model. This was accompanied by a marked reduction in molecular and histological hallmarks of cardiac damage, including hypertrophy, inflammation, fibrosis, and cardiomyocyte apoptosis.
Conclusion
These findings identify MALT1 as a key mediator of immune-driven myocardial injury and suggest that selective MALT1 inhibition may represent a promising therapeutic approach for autoimmune myocarditis.