A CCR1 antagonist prevents the development of experimental autoimmune myocarditis in association with T cell
Hideki Futamatsu1, Jun-ichi Suzuki, Noritaka Koga
1Department of Cardiovascular Medicine, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
Abstract:
Chemokines play an important role in induction of chemotaxis of immune cells. CCR1 is a chemokine receptor expressed on neutrophils, monocytes, and T lymphocytes. The role of CCR1 in immunity is not well examined. We demonstrated the role of CCR1 on T lymphocytes and the effect of a CCR1 antagonist, BX471 in myocarditis. Lewis rats were immunized with cardiac myosin on day 0 to establish experimental autoimmune myocarditis. Rats were then administered BX471 subcutaneously every day (group BX0: n = 7) or from day 14 (group BX14: n = 7) and were killed on day 21. We confirmed expression of CCR1 in cells infiltrating the myocardium by immunohistochemistry and FACS analysis. The development of myocarditis was almost completely prevented in group BX0, and myocarditis-affected areas were significantly decreased in size in group BX14. Cardiac function was markedly improved. Ribonuclease protection assay showed that the CCR1 antagonist treatment suppressed mRNA expression for IL-6, IL-1beta, and TNF-alpha in the hearts. An antigen-specific T cell proliferation assay was performed with CD4-positive T cells isolated from control rats immunized with cardiac myosin. T cell proliferation was inhibited by the CCR1 antagonist. Additionally, we showed by Western blot that the CCR1 antagonist suppressed ERK1/2 and JNK activities in T cells stimulated with myosin and that IL-2 reversed this suppression. The CCR1 antagonist reduced the severity of EAM by inhibiting cytokine expression and inducing T cell inactivation. Thus, the CCR1 antagonist may provide a novel therapeutic strategy treatment of myocarditis.
Insights
A CCR1 antagonist, BX471, significantly reduced experimental autoimmune myocarditis severity in rats. This novel therapeutic strategy inhibits cytokine expression and inactivates T cells, offering potential treatment for myocarditis.
Area of Science:
- Immunology
- Cardiovascular Research
- Pharmacology
Background:
- Chemokines and their receptors, like CCR1, are crucial for immune cell migration.
- The specific role of CCR1 in T lymphocytes and its therapeutic potential in myocarditis remain underexplored.
Purpose of the Study:
- To investigate the role of CCR1 in T lymphocytes during experimental autoimmune myocarditis (EAM).
- To evaluate the therapeutic efficacy of a CCR1 antagonist (BX471) in a rat model of myocarditis.
Main Methods:
- Experimental autoimmune myocarditis was induced in Lewis rats using cardiac myosin immunization.
- Rats were treated with the CCR1 antagonist BX471, and disease severity was assessed.
- Immunohistochemistry, FACS analysis, ribonuclease protection assays, and Western blotting were used to analyze CCR1 expression, cytokine mRNA levels, and T cell signaling pathways.
Main Results:
- BX471 treatment significantly prevented or reduced myocarditis development and cardiac damage.
- The antagonist suppressed pro-inflammatory cytokine mRNA (IL-6, IL-1beta, TNF-alpha) in the heart.
- BX471 inhibited antigen-specific T cell proliferation and suppressed ERK1/2 and JNK activities in T cells.
Conclusions:
- CCR1 plays a significant role in T lymphocytes during autoimmune myocarditis.
- The CCR1 antagonist BX471 demonstrates therapeutic potential by reducing inflammation and improving cardiac function.
- BX471 may represent a novel therapeutic strategy for treating myocarditis by modulating immune cell responses.
