Abstract
Autoantibodies against the M2 receptors (M2AChR) have been associated with Dilated Cardiomyopathy (DCM). In the heart, P2×7 receptors influence electrical conduction, coronary circulation and response to ischemia. They can also trigger pro-inflammatory responses and the development of neurological, cardiac and renal disorders. Here, P2×7−/− mice displayed an increased heart rate and ST segment depression, but similar exercise performance when compared to wild type (WT) animals. After immunization with plasmid containing M2AChR cDNA sequence, WT mice produced anti-M2AChR antibodies, while P2×7−/− mice showed an attenuated production. Despite this, WT and P2×7−/− showed left ventricle cavity enlargement and decreased exercise tolerance. Transfer of serum from M2AChR WT immunized mice to näive recipients led to an alteration in heart shape. P2×7−/− mice displayed a significant increase in the frequency of spleen regulatory T cells population, which is mainly composed by the FoxP3+CD25− subset. M2AChR WT immunized mice showed an increase in IL-1β, IFNγ and IL-17 levels in the heart, while P2×7−/− group produced lower amounts of IL-1β and IL-17 and higher amounts of IFNγ. These results pointed to previously unnoticed roles of P2×7 in cardiovascular and immune systems, and underscored the participation of IL-17 and IFNγ in the progress of autoimmune DCM.
Highlights
IntroductionA series of experiments have established the involvement of IFNγ and IL-17 in autoimmune disorders and their severity[9,10]
This finding was well reported by using Ifng−/− mice that showed an increased in heart dilatation and Left Ventricle (LV) mass increment around the 23th day[15,16,17]
M2AChR wild type (WT – full black lines) mice produced higher levels of anti-M2AChR antibodies from the 5th week post-immunization as compared to the control animals immunized with the empty pcDNA3 plasmid (Fig. 1 – full grey lines)
Summary
A series of experiments have established the involvement of IFNγ and IL-17 in autoimmune disorders and their severity[9,10] These cytokines are produced mainly by Th1 and Th17 cells, respectively[11], in some instances it is possible to observe a shift from Th17 cells to a Th1 phenotype, where Th17 cells can synthesize IFNγ 12,13. In experimental autoimmune myocarditis model (EAM) using myocardiotogenic peptide derived from alpha-cardiac myosin heavy chain accompanied for 62 days, IFNγ presented a protective role This finding was well reported by using Ifng−/− mice that showed an increased in heart dilatation and Left Ventricle (LV) mass increment around the 23th day[15,16,17]. These results suggest that the balance of these two cytokines may influence the evolution of dilated cardiac pathogenesis
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