MyD88 Signaling Controls Autoimmune Myocarditis Induction

Abstract

Background— Experimental autoimmune myocarditis (EAM) is a CD4 + T-cell–mediated mouse model of postviral cardiomyopathy. Activation of interleukin-1 type 1 and Toll-like receptors that share the common downstream adaptor molecule MyD88 is required for disease induction. The specific role of MyD88 in myocarditis, however, is not known. Methods and Results— In contrast to control littermates, MyD88 −/− mice were protected from myocarditis after immunization with α-myosin heavy chain–derived peptide (MyHC-α) and complete Freund’s adjuvant. Disease resistance of MyD88 −/− mice resulted from impaired expansion of heart-specific CD4 + T cells after immunization. Intrinsic defects of MyD88 −/− CD4 + T cells were excluded. In contrast, MyD88 −/− but not MyD88 +/+ primary antigen presenting dendritic cells (DCs) were defective in their capacity to prime CD4 + T cells. This defect mainly resulted from the inability of MyD88 −/− DCs to release tumor necrosis factor-α. The critical role of MyD88 signaling in DCs in the peripheral lymphatic compartments was finally proven by repetitive injection of activated, MyHC-α–loaded MyD88 +/+ DCs that fully restored T-cell expansion and myocarditis in MyD88 −/− mice. Conclusions— Autoimmune myocarditis induction depends on MyD88 signaling in self-antigen presenting cells in the peripheral compartments. We conclude that MyD88 might become a target for prevention of heart-specific autoimmunity and cardiomyopathy.

Suppressor of Cytokine Signaling 1 DNA Administration Inhibits Inflammatory and Pathogenic Responses in Autoimmune Myocarditis

“…Furthermore, IL-1 type 1 receptor signaling on DCs is critical for autoimmune myocarditis development (11). MyD88 is a crucial common adaptor molecule that mediates both TLRs and IL-1 type 1 receptor activation (46,47), and MyD88 signaling in DCs is critical for the induction of EAM (16). SOCS1 negatively regulates the MyD88-dependent pathway by interacting with both IL-1R-associated kinase and NF-kB (17), which results in a decrease in the induction of inflammatory cytokines such as TNF-a and IL-6.…”

“…EAM is a CD4 + T cell-mediated disease (7,14), and activation of self-Ag-loaded dendritic cells (DCs) is critical for expansion of autoreactive CD4 + T cells. Activation of TLRs and IL-1 type 1 receptor and their common downstream signaling adaptor molecule, MyD88, in self-Ag-presenting DCs is also critical for the development of EAM (11,15,16). Compared with inhibition of a single cytokine, a more effective treatment might be inhibition of various signaling pathways to induce production of cytokines through both innate and adaptive immunity.…”

CD11b+ Monocytes Abrogate Th17 CD4+ T Cell-Mediated Experimental Autoimmune Myocarditis

“…EAM can be induced in susceptible mouse strains by immunization with self-peptides derived from the myosin ␣ H chain (MyHC-␣) together with a strong adjuvant (7,8), or by injection of activated, MyHC-␣-loaded dendritic cells (9,10). In wild-type mice, disease severity peaks 2-3 wk after immunization.…”

Myeloid Differentiation Factor-88/Interleukin-1 Signaling Controls Cardiac Fibrosis and Heart Failure Progression in Inflammatory Dilated Cardiomyopathy

“…[7][8][9][10][11] We found that cardiac damage of any cause, together with nonspecific activation of APCs via Toll-like receptors (TLRs) is sufficient to break immunotolerance. 12,13 Accordingly, activated bone marrow-derived dendritic cells (bmDCs) loaded with ␣-myosin heavy chain (MyHC-␣) peptide induce acute CD4 ϩ T cell-mediated myocarditis in susceptible mice. 12,13 IL-1 receptor and most of the TLRs share the common downstream signaling adaptor molecule MyD88.…”

“…12,13 Accordingly, activated bone marrow-derived dendritic cells (bmDCs) loaded with ␣-myosin heavy chain (MyHC-␣) peptide induce acute CD4 ϩ T cell-mediated myocarditis in susceptible mice. 12,13 IL-1 receptor and most of the TLRs share the common downstream signaling adaptor molecule MyD88. 14,15 MyD88-and IL-1 receptor (IL-1R) signaling on APCs are critical for the induction of heart-specific T-cell responses and EAM.…”