Toll-like receptor signaling: a critical modulator of cell survival and ischemic injury in the heart

Abstract

Toll-like receptors (TLRs) represent the first line of host defense against microbial infection and play a pivotal role in both innate and adaptive immunity. TLRs recognize invading pathogens through molecular pattern recognition, transduce signals via distinct intracellular pathways involving a unique set of adaptor proteins and kinases, and ultimately lead to the activation of transcription factors and inflammatory responses. Among 10 TLRs identified in humans, at least two exist in the heart, i.e., TLR2 and TLR4. In addition to the critical role of these in mediating cardiac dysfunction in septic conditions, emerging evidence suggests that the TLRs can also recognize endogenous ligands and may play an important role in modulating cardiomyocyte survival and in ischemic myocardial injury. In animal models of ischemia-reperfusion injury or in hypoxic cardiomyocytes in vitro, the administration of a sublethal dose of lipopolysaccharide, which signals through TLR4, reduces subsequent myocardial infarction, improves cardiac functions, and attenuates cardiomyocyte apoptosis. By contrast, a systemic deficiency of TLR2, TLR4, or myeloid differentiation primary-response gene 88, an adaptor critical for all TLR signaling, except TLR3, leads to an attenuated myocardial inflammation, a smaller infarction size, a better preserved ventricular function, and a reduced ventricular remodeling after ischemic injury. These loss-of-function studies suggest that both TLRs contribute to myocardial inflammation and ischemic injury in the heart although the exact contribution of cardiac (vs. circulatory cell) TLRs remains to be defined. These recent studies demonstrate an emerging role for TLRs as a critical modulator in both cell survival and tissue injury in the heart.

Up‐regulated TLR4 in cardiomyocytes exacerbates heart failure after long‐term myocardial infarction

“…Most of the studies addressing cardiomyocyte TLR4 were performed in models of acute ischaemia/reperfusion. While multiple studies show that systemic deficiency of TLR4 alleviates myocardial inflammation and injury following acute ischaemia/reperfusion 7, 11, 33, controversies exist as to the causal role of cardiomyocyte TLR4 ( versus leucocyte TLR4). In isolated perfused mouse heart subjected to global ischaemia and reperfusion, Ao et al .…”

The global diabetes epidemic as a consequence of lifestyle-induced low-grade inflammation

“…Thus, high glucose or saturated fat stress probably gives rise to the production of endogenous ligands for TLR4. Interestingly, tissue damage in response to ischaemia-reperfusion also requires intact TRL4, again indicating that endogenous TLR4 ligands are produced during local stress [98]. We have previously identified heat shock protein 60 as one such 'danger antigen' [99].…”

Antioxidant defenses in diabetes mellitus: a clinical and molecular approach

“…Hyperglycemia also triggers activation of the Toll-like receptors-4 (TLR4) in myocardiocytes membrane, a cell surface receptor responsible for pathogen recognition by the immune cells [100]. In this study, the inhibition of TLR4 blocks apoptosis, NADPH oxidase activity and free radical release in cardiomyocytes.…”