Myeloid differentiation factor-88 contributes to TLR9-mediated modulation of acute coxsackievirus B3-induced myocarditis in vivo

Riad A, Westermann D, Escher F, Becher PM, Savvatis K, Lettau O, Heimesaat MM, Bereswill S, Volk HD, Schultheiss HP, Tschope C. Myeloid differentiation factor-88 contributes to TLR9-mediated modulation of acute coxsackievirus B3-induced myocarditis in vivo. Am J Physiol Heart Circ Physiol 298: H2024-H2031, 2010. First published March 12, 2010; doi:10.1152/ajpheart.01188.2009.-Toll-like receptor 9 (TLR9) is a member of the innate immune system and has been shown to influence myocardial function, but its role in myocarditis is hitherto unknown. We therefore investigated whether or not TLR9 plays a role in this disease in coxsackievirus B3 (CVB3)-induced myocarditis in mice. Left ventricular (LV) function, cardiac immune cell infiltration, virus mRNA, and components of the TLR9 downstream pathway were investigated in TLR9-deficient [knockout (KO)] and wild-type (WT) mice after infection with CVB3. Murine cardiac TLR9 expression was significantly increased in WT mice with acute CVB3 infection but not in WT mice with chronic myocarditis. Furthermore, in the acute phase of CVB3-induced myocarditis, CVB3-infected KO mice displayed improved LV function associated with reduced cardiac inflammation indexed by reduced amounts of immune cells compared with CVB3-infected WT mice. In contrast, in the chronic phase, LV function and inflammation were not seen to differ among the infected groups. The cardioprotective effects due to TLR9 deficiency were associated with suppression of the TLR9 downstream pathway as indexed by reduced cardiac levels of the adapter protein myeloid differentiation factor (MyD)-88 and the proinflammatory cytokine TNF-alpha. In addition, TLR9 deficiency led to an activation of the antiviral cytokine interferon-beta in the heart as a result from viral infection. In conclusion, the MyD88/TNF-alpha axis due to TLR9 activation in the heart contributes the development of acute myocarditis but not of chronic myocarditis.