Abstract
Toll-like receptors (TLRs) are evolutionary conserved molecules that recognize various microbial components and host-derived agonists from damaged cells and play a central role in innate and adaptive immunity. It has been reported that MyD88, the adaptor molecule downstream of all TLRs, except TLR3, is essential for initiation of experimental autoimmune myocarditis (EAM). To determine the role of the intracellular TLRs in EAM, TLR3− / − , TLR7− / − , and TLR9− / − mice were immunized with cardiac α-myosin heavy chain peptide (MyHC-α) in Complete Freund's Adjuvant (CFA) and their EAM scores and associated immunological responses were compared to wild-type (WT) and MyD88− / − mice. MyD88− / − mice were completely resistant to EAM and had a profound defect in all the parameters we tested. Myocardial cellular infiltration and in vitro proliferation of MyHC-α-restimulated splenocytes were markedly reduced in TLR7− / − mice, while TLR3− / − and TLR9− / − mice showed similar inflammatory cell infiltration in the heart-like WT mice. Thus, the resistance of MyD88− / − mice to EAM can be attributed to a certain degree to TLR7 signaling. Moreover, upon murine cytomegalovirus-induced myocarditis, we found that the severity of myocardial inflammation was higher in TLR9− / − and MyD88− / − mice compared with WT, TLR3− / − , or TLR7− / − mice and paralleled the ability of the mice to fight the viral infection.
Acknowledgments
We thank S. Akira for providing the TLR9− / − and MyD88− / − mice Citation[26,32], H. Farrell for providing the MCMV strain K181, the personnel of the animal facility Laboratoire d'Exploration Fonctionelle Service inter-IFR for taking care of the mice, L. Chasson and the mouse functional genomics platform of the Marseille-Nice Genopole for immunohistochemistry with support from the INCA PROCAN program.
Declaration of interest: P.P. Pagni received a PhD fellowship from Région Provence-Alpes-Côte d'Azur co-financed by Innate Pharma. L. Alexopoulou is supported by an ATIP plus grant from the Centre National de la Research Scientific. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.