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.

Fig. 1.

Toll-like receptor (TLR) signaling. All TLRs are transmembrane proteins with a large extra-cellular domain containing leucine-rich repeats and a unique cytoplasmic Toll/IL-1 receptor (TIR) domain. TLRs exist in dimmers, and all TLR family members, except TLR3, signal through the key adaptor myeloid differentiation primary-response gene 88 (MyD88) to recruit downstream interleukin (IL)-1 receptor-associated kinases (IRAKs). In some TLR signaling, such as TLR2 and TLR4, MyD88 adaptor-like protein (Mal) is required for recruiting MyD88 to their receptors, whereas in others, such as TLR5, TLR7, TLR9, and TLR11, Mal is not required. TLR1 and TLR2 or TLR2 and TLR6 form heterodimers that signal through Mal/MyD88. TLR3 signals through the adaptor TIR-domain-containing adaptor protein inducing interferon-β (IFN-β)-mediated transcription-factor (Trif), which recruits and activates TNF receptor-associated factor-family member-associated NF-κB activator-binding kinase 1 (TBK1). In addition to Mal/MyD88-dependent pathway, TLR4 can also signal through a MyD88-independent pathway that activates TBK1 via Trif-related adaptor molecule (TRAM)-Trif-dependent mechanism. TLR5, TLR7/8, TLR9, and TLR11 use only MyD88 as its signaling adaptor. These kinases ultimately activate transcription factors such as nuclear factor-κB (NF-κB) and IFN regulatory factor (IRFs), which result in production of various proinflammatory cytokines such as tumor necrosis factor (TNF), ILs, and IFNs.