RESUMEN
BACKGROUND: Staphylococcus aureus sepsis is associated with significant myocardial dysfunction. Toll-like receptor 2 (TLR2) mediates the inflammatory response to S aureus and may trigger an innate immune response in the heart. We hypothesized that a TLR2 deficiency would attenuate S aureus-induced cardiac proinflammatory mediator production and the development of cardiac dysfunction. METHODS AND RESULTS: Wild-type and TLR2-deficient (TLR2D) mice were studied. S aureus challenge significantly increased tumor necrosis factor, interleukin-1beta, and nitric oxide expression in hearts of wild-type mice. This response was significantly blunted in TLR2D mice. Hearts from TLR2D mice had impaired S aureus-induced activation of interleukin-1 receptor-associated kinase, c-Jun NH2 terminal kinase, nuclear factor-kappaB, and activator protein-1. Moreover, hearts from TLR2D mice were protected against S aureus-induced contractile dysfunction. CONCLUSIONS: These results show for the first time that TLR2 signaling contributes to the loss of myocardial contractility and cytokine production in the heart during S aureus sepsis.
Asunto(s)
Citocinas/biosíntesis , Miocardio/metabolismo , Receptores de Superficie Celular/fisiología , Infecciones Estafilocócicas/complicaciones , Staphylococcus aureus/patogenicidad , Disfunción Ventricular Izquierda/metabolismo , Disfunción Ventricular Izquierda/fisiopatología , Animales , Niño , GMP Cíclico/biosíntesis , Corazón/fisiopatología , Humanos , Interleucina-1/biosíntesis , Ratones , Ratones Noqueados , Contracción Miocárdica , Óxido Nítrico/biosíntesis , Receptores de Superficie Celular/genética , Transducción de Señal , Staphylococcus aureus/aislamiento & purificación , Receptor Toll-Like 2 , Factor de Necrosis Tumoral alfa/biosíntesis , Disfunción Ventricular Izquierda/etiologíaRESUMEN
Enterovirus-induced myocardial injury can lead to severe heart failure. To date, little is known about the early innate stress response that contributes to host defense in the heart. Toll-like receptor 3 (TLR3) is important in the initiation of the innate antiviral response. We investigated the involvement of TLR3, which recognizes viral double-stranded RNA, on encephalomyocarditis virus (EMCV) infection. To examine the contribution of TLR3 in protection from EMCV infection, we infected mice deficient in TLR3 with 50 plaque-forming units of EMCV. TLR3-deficient (TLR3(-/-)) mice were more susceptible to EMCV infection and had a significantly higher viral load in the heart compared with TLR3(+/+) mice. Histopathological examination showed that the inflammatory changes of the myocardium were less marked in TLR3(-/-) than in TLR3(+/+)mice. TLR3(-/-) mice had impaired proinflammatory cytokine and chemokine expression in the heart following EMCV infection. However, the expression of interferon-beta was not impaired in EMCV-infected TLR3(-/-) mice. EMCV infection leads to a TLR3-dependent innate stress response, which is involved in mediating protection against virus-induced myocardial injury.