Therapeutic targeting of innate immunity in the failing heart

Abstract

Recent studies suggest that the heart possesses an intrinsic system that is intended to delimit tissue injury, as well as orchestrate homoeostatic responses within the heart. The extant literature suggests that this intrinsic stress response is mediated, at least in part, by a family of pattern recognition receptors that belong to the innate immune system, including CD14, the soluble pattern recognition receptor for lipopolysaccharide, and Toll-like receptors 2, 3, 4, 5, 6, 7, and 9. Although this intrinsic stress response system provides a short-term adaptive response to tissue injury, the beneficial effects of this phylogenetically ancient system may be lost if myocardial expression of these molecules either becomes sustained and/or excessive, in which case the salutary effects of activation of these pathways are contravened by the known deleterious effects of inflammatory signaling. Herein we present new information with regard to activation of innate immune gene expression in the failing human heart, as well as review the novel TLR antagonists that are being developed for other indications outside of heart failure. This review will discuss the interesting possibility that the TLR pathway may represent a new target for the development of novel heart failure therapeutics. This article is part of a special issue entitled "Key Signaling Molecules in Hypertrophy and Heart Failure."

Figure 1

The Toll-like receptor signaling pathway. (Key: AP1, activator protein 1; HSP-60, heat shock protein 60; IκB, inhibitor of nuclear factor κB; IKKα, inhibitor of nuclear factor κ-B kinase α; IKKß, inhibitor of nuclear factor κB kinase-ß; IKKε, inhibitor of nuclear factor κ-B kinase ε; IKKγ, inhibitor of nuclear factor κ-B kinase γ; IRAK1, interleukin 1 receptor-associated kinase 1; IRAK4, interleukin 1 receptor-associated kinase 4; IRF3, interferon regulatory factor 3; IRF5, interferon regulatory factor 5; JNK, c-jun N-terminal kinase; LPS, lipopolysaccharide; MyD88, myeloid differentiation primary response protein; NF-κB, nuclear factor κB; RIP1, receptor-interacting protein 1; TAB1, TAK1 - binding protein 1; TAB2-TAB3, TAK1 -binding proteins 2 and 3; TAK1 (M3K7), transforming growth factor-ß-activated kinase 1; TBK1, serine-threonine-protein kinase; TIRAP, TIR domain-containing adaptor protein; TLR4, Toll-like receptor 4; TRAF6, tumor necrosis factor receptor-associated factor 6; TRAM, TRIF-related adaptor molecule; TRIF, TIR-domain-containing adaptor inducing interferon ß; Ub, ubiquitin; UB2V1, ubiquitin-conjugating enzyme E2 variant 1; UBE2N, ubiquitin-conjugating enzyme E2N (Reproduced with permission from Frantz, S., Ertl, G., & Bauersachs, J. Mechanisms of disease: Toll-like receptors in cardiovascular disease. Nat.Clin.Pract.Cardiovasc.Med. 4, 444-454, 2007).

Figure 2

Principal component analysis of changes in innate immune gene expression in failing and non-failing human hearts. Innate immune genes were subjected to a principal component analysis (PCA), and the first, second and third principal components were displayed in a 3-D graphic format. (From Mann DL, Topkara VK, Evans S, Barger PM. Innate immunity in the adult Mammalian heart: for whom the cell tolls. Trans Am Clin Climatol Assoc 2010;121:34-50).