TLR3 deficiency induces chronic inflammatory cardiomyopathy in resistant mice following coxsackievirus B3 infection: role for IL-4

Abstract

Recent findings indicate that TLR3 polymorphisms increase susceptibility to enteroviral myocarditis and inflammatory dilated cardiomyopathy (iDCM) in patients. TLR3 signaling has been found to inhibit coxsackievirus B3 (CVB3) replication and acute myocarditis in mouse models, but its role in the progression from myocarditis to iDCM has not been previously investigated. In this study we found that TLR3 deficiency increased acute ( P = 5.9 × 10−9) and chronic ( P = 6.0 × 10−7) myocarditis compared with WT B6.129, a mouse strain that is resistant to chronic myocarditis and iDCM. Using left ventricular in vivo hemodynamic assessment, we found that TLR3-deficient mice developed progressively worse chronic cardiomyopathy. TLR3 deficiency significantly increased viral replication in the heart during acute myocarditis from day 3 through day 12 after infection, but infectious virus was not detected in the heart during chronic disease. TLR3 deficiency increased cytokines associated with a T helper (Th)2 response, including IL-4 ( P = 0.03), IL-10 ( P = 0.008), IL-13 ( P = 0.002), and TGF-β1 ( P = 0.005), and induced a shift to an immunoregulatory phenotype in the heart. However, IL-4-deficient mice had improved heart function during acute CVB3 myocarditis by echocardiography and in vivo hemodynamic assessment compared with wild-type mice, indicating that IL-4 impairs cardiac function during myocarditis. IL-4 deficiency increased regulatory T-cell and macrophage populations, including FoxP3+ T cells ( P = 0.005) and Tim-3+ macrophages ( P = 0.004). Thus, TLR3 prevents the progression from myocarditis to iDCM following CVB3 infection by reducing acute viral replication and IL-4 levels in the heart.

Enterovirus 68 3C Protease Cleaves TRIF To Attenuate Antiviral Responses Mediated by Toll-Like Receptor 3

“…Several lines of evidence demonstrate that TLR3 plays a role in the antiviral response against enterovirus infections (31)(32)(33)(34)(35)(36)(37). Rhinovirus infection is recognized initially by TLR3 (38).…”

In VivoAblation of Type I Interferon Receptor from Cardiomyocytes Delays Coxsackieviral Clearance and Accelerates Myocardial Disease

“…Genetic analysis of patients with enteroviral myocarditis revealed a rare variant of one sensor, TLR3, at amino acid (aa) 554, as well as a TLR3 polymorphism (L/F at aa 412) in which the F/F genotype was twice as common in patients as in controls; both TLR3 proteins (aa 554 and F 412 ) showed reduced T1IFN signaling in tissue culture (74,75). TLR3-deficient mice are more susceptible to CVB3 infection (63,76,77), as are mice deficient in other molecules that are involved in T1IFN production, such as TLR7 (78), MDA5 (79,80), MAVS (79), TRIF (76,81,82), and MyD88 (83,84). Furthermore, clinical studies have demonstrated the utility of IFN-␤ in treating enteroviral myocarditis (44,45).…”

Myocarditis

“…160 Animal studies using TLR3-and TLR4-deficient mice demonstrate a protective function for both TLR3 and TLR4 in CVB3-induced myocarditis and DCM. [161][162][163] Moreover, animal studies suggest that sex differences in TLR signaling play an important role in differential susceptibility to CVB3-induced myocarditis in men and women. 21,164,165 The antiviral significance of IFNs has also been observed at the level of their gene targets.…”