Innate immunity in the adult mammalian heart: for whom the cell tolls

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, and 6. 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 may be 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. Taken together, these new observations provide provisional evidence that the innate immune system is activated in human heart failure, raising the interesting possibility that this pathway may represent a target for the development of novel heart failure therapeutics.

Fig. 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; IKKβ, inhibitor of nuclear factor κB kinase-β; 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-β-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 β; 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).

Fig. 2

Principal component analysis of changes in innate immune gene expression in failing and non-failing human hearts. Innate immune genes (Table 2) were subjected to a principal component analysis (PCA), and the first, second and third principal components were displayed in a 3-D graphic format (see Data Supplement for details). The 3-dimensional PCA analyses depicted in this figure accounted for 36.6% of the total variation of the entire data set.

Fig. 3

Hierarchical cluster analysis of innate immune genes. An unsupervised hierarchical cluster analysis was performed on the family of innate immune genes depicted in Table 2. Increased gene expression is depicted in red, and decreased gene expression is depicted in blue.

Fig. 4

Venn diagram of changes in gene expression that are common and unique to ischemic (ICM), idiopathic dilated (DCM) and viral cardiomyopathy (VCM). ANOVA testing was performed on the change in gene expression in DCM, ICM, and VCM hearts, relative to NF hearts, for the ensemble of innate immune genes displayed in Table 2. There were 37, 37, and 27 transcripts, respectively, in DCM, ICM, and VCM hearts. The Venn diagram depicts the number of innate immune genes whose changes in gene expression that are common to all forms of cardiomyopathy (n = 14), those that are common to DCM and ICM (n = 21 [14 + 7]), those that are common to ICM and VCM (n = 22 [14 + 8), those that are common to VCM and ICM (n = 15 [14 + 1]), and those that are unique to DCM alone (n = 8), those that are unique to ICM (n = 15), and those that are unique to VCM (n = 4).

Fig. 5

Functional significance of changes in innate immune gene expression in human heart failure. Changes in innate immune gene expression in ischemic, idiopathic dilated and viral cardiomyopathies were compared to non-failing hearts for the transcripts shown in Table 2 and were projected onto a map of Toll-like receptor (TLR) signaling. Increased gene expression is depicted in red, decreased gene expression is depicted in blue, and no change in gene expression is depicted as an open symbol. Changes in ischemic cardiomyopathy are depicted as an open symbols, changes in idiopathic cardiomyopathy is depicted as an square symbols, and changes in viral cardiomyopathy are depicted as triangles.