MyD88 activation in cardiomyocytes contributes to the heart immune response to acute Trypanosoma cruzi infection with no effect on local parasite control

Abstract

Cardiomyopathy is the most serious consequence of Chagas disease, a neglected human disorder caused by Trypanosoma cruzi infection. Because T. cruzi parasites invade cardiomyocytes, we sought to investigate whether these cells recognize the parasite in vivo by receptors signaling through the MyD88 adaptor, which mediates the activation pathway of most Toll-like receptors (TLRs) and IL-1/IL-18 receptors, and influence the development of acute cardiac pathology. First, we showed that HL-1 cardiac muscle cell line expresses MyD88 gene and protein at resting state and after T. cruzi infection. To evaluate the role in vivo of MyD88 expression in cardiomyocytes, we generated Mer+MyD88flox+/+ mice in which tamoxifen treatment is expected to eliminate the MyD88 gene exclusively in cardiomyocytes. This Cre-loxP model was validated by both PCR and western blot analysis; tamoxifen treatment of Mer+MyD88flox+/+ mice resulted in decreased MyD88 gene and protein expression in the heart, but not in the spleen, while had no effect on littermates. The elimination of MyD88 in cardiomyocytes determined a lower increase in CCL5, IFNγ and TNFα gene transcription during acute infection by T. cruzi parasites of the Y strain, but it did not significantly modify heart leukocyte infiltration and parasitism. Together, our results show that cardiomyocytes can sense T. cruzi infection through MyD88-mediated molecular pathways and contribute to the local immune response to the parasite. The strong pro-inflammatory response of heart-recruited leukocytes may overshadow the effects of MyD88 deficiency in cardiomyocytes on the local leukocyte recruitment and T. cruzi control during acute infection.

Circular RNA circ‐RCCD promotes cardiomyocyte differentiation in mouse embryo development via recruiting YY1 to the promoter of MyD88

“…It is reported that MyD88 plays a vital role in the development of heart disease 15,16 . So, we used Western blot assay to explore the expression of MyD88 in DMSO‐induced P19 cells.…”

“…It is reported that MyD88 plays a vital role in the development of heart disease. 15 , 16 So, we used Western blot assay to explore the expression of MyD88 in DMSO‐induced P19 cells. Results showed that both mRNA and protein expression of MyD88 in p19 cells were down‐regulated at 0, 4, 6 and 10 days after DMSO stimulation (Figure 3A,B ).…”

Avaliação do papel de moléculas purinérgicas P2X7 e CD39 em resposta ao >i<Trypanosoma cruzi>/i< na fase aguda de infecção cardíaca

“…Além disto, em relação a estudos in vivo, o nosso grupo de pesquisa mostrou recentemente que os cardiomiócitos, principais vítimas na CCC, também contribuem in vivo à resposta imune cardíaca contra o parasito. Assim, no animal infectado pelo T. cruzi por um período de 10-30 dias foi observado que os cardiomiócitos são ativados através de receptores que utilizam o adaptador MyD88, sinalização que resulta em aumento significativo da produção local de quimiocinas e citocinas (Santana et al, 2018).…”