Toll-like receptors in atherosclerosis

Abstract

Atherosclerosis, the leading cause of cardiovascular disease (CVD), is driven by inflammation. Increasing evidence suggests that toll-like receptors (TLRs) are key orchestrators of the atherosclerotic disease process. Interestingly, a distinct picture is being revealed for individual receptors in atherosclerosis. TLRs exhibit a complex nature enabling the detection of multiple motifs named danger-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs). Activation of these receptors triggers an intracellular signalling cascade mediated through MyD88 or TRIF, leading to the production of pro- and anti-inflammatory cytokines. In this review we explore key novel findings pertaining to TLR signalling in atherosclerosis, including recently described endosomal TLRs and future directions in TLR research.

Figure 1

TLR signalling pathways. MyD88 is an adaptor protein, critical in mediating the signalling of all TLRs except TLR3. TIRAP/MAL participates in TLR2 and TLR4 MyD88-mediated signal transduction, in that its C-terminus TIRAP/MAL-TIR bridges TLR2 and TLR4 with MyD88 [56,57]. In addition to a TIR-domain, MyD88 harbours a death domain (DD). Upon PAMP recognition by TLRs, its DD interacts with the DD of a member of the IL-1 receptor-associated kinase (IRAK) family, IRAK-4, which consists of a DD and a kinase-like domain. The formation of the MyD88-IRAK-4 complex recruits IRAK-1 and IRAK-2, bringing their kinase-like domains close, resulting in phosphorylation of IRAKs and their subsequent activation. Phosphorylated IRAK-1 or IRAK-2 leave the complex and interact with tumour necrosis factor receptor associated factor 6 (TRAF6), an E3 ubiquitin ligase, to generate Lys63-linked polyubiquitination [58,59]. These polyubiquitin chains bind a complex of TGF-β activated kinase-1 (TAK-1) and TAK-1 binding proteins (TAB) 1, 2 and 3—resulting in TAK1 activation. Activated TAK-1 phosphorylates IKKβ. The subsequent activation of the IKK complex, consisting of IKKα, IKKβ, and NEMO/IKKγ, induces phosphorylation of IKKα and MAP kinases, allowing for the activation of transcription factors and production of inflammatory cytokines.