Contribution of TLR7 and TLR9 signaling to the susceptibility of MyD88-deficient mice to myocarditis.
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 alpha-myosin heavy chain peptide (MyHC-alpha) 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-alpha-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.
Pagni
Philippe P
PP
Centre d'Immunologie de Marseille-Luminy, Marseille, France.
Traub
Stephanie
S
Demaria
Olivier
O
Chasson
Lionel
L
Alexopoulou
Lena
L
D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology / Q000821:virology; D004198:Disease Susceptibility / Q000276:immunology; D005260:Female; D006321:Heart / Q000821:virology; D007249:Inflammation / Q000276:immunology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D018146:Muromegalovirus / Q000472:pathogenicity*; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D009205:Myocarditis / Q000276:immunology / Q000821:virology; D009206:Myocardium / Q000276:immunology; D015398:Signal Transduction; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000378:metabolism*; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000378:metabolism*
D008562:Membrane Glycoproteins; D053594:Myeloid Differentiation Factor 88; C477038:Tlr7 protein, mouse; C495370:Tlr9 protein, mouse; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9