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

Abstract

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.

Innate immune receptors in heart failure: Side effect or potential therapeutic target?

“…TLR7 and TLR9 contribute to the susceptibility of MyD88-deficient mice in experimental myocarditis [76] . This is also strengthened by our finding that shows that MyD88 may contribute to the modulation of TLR9 in CVB3-induced myocarditis in mice [77] . In another study, infection of TLR3-deficient mice with encephalomyocarditis virus (EMCV)-a ssRNA virus-interestingly led to earlier death in knock-out mice, combined with increased viral replication and myocardial injury [78] .…”

Chronic Heart Failure and Inflammation

“…150,151 Depletion of monocytes, macrophages, and DCs also causes death during viral myocarditis; however, blunting monocyte activation and macrophage expansion have also been shown to be beneficial, suggesting that the exact role of monocytes, macrophages, and DCs remains to be defined. 150 Because different cardiac macrophage lineages exist, some of which are monocyte derived, whereas others are embryonic derived and possess reparative functions, understanding the role of each macrophage lineage may yield additional clarity to this field.…”

Autoantibodies in Heart Failure and Cardiac Dysfunction

“…22 In coxsackievirus B3 (CVB3)-induced myocarditis in mice, the TLR-9 mediated activation of MyD88 with subsequent activation of TNF-␣ contributes to the development of acute myocarditis. 23 Further, the severity of myosin-induced experimental autoimmune myocarditis has been shown to be dependent on TLR-7 triggered MyD88 activation. 24 The role of TLRsignaling in human heart failure however is poorly understood.…”