Endocytosed HSP60s Use Toll-like Receptor 2 (TLR2) and TLR4 to Activate the Toll/Interleukin-1 Receptor Signaling Pathway in Innate Immune Cells

Abstract

Heat shock proteins (HSPs) require no adjuvant to confer immunogenicity to bound peptides, as if they possessed an intrinsic "danger" signature. To understand the proinflammatory nature of HSP, we analyzed signaling induced by human and chlamydial HSP60. We show that both HSP60s activate the stress-activated protein kinases p38 and JNK1/2, the mitogen-activated protein kinases ERK1/2, and the I-B kinase (IKK). Activation of JNK and IKK proceeds via the Toll/IL-1 receptor signaling pathway involving MyD88 and TRAF6. Human fibroblasts transfected with TLR2 or TLR4 plus MD-2 gain responsiveness to HSP60, while TLR2-or TLR4-defective cells display impaired responses. Initiation of signaling requires endocytosis of HSP60 that is effectively inhibited by serum component(s). The results revealed that adjuvanticity of HSP60 operates similar to that of classical pathogen-derived ligands.

Increased macrophage activation mediated through toll‐like receptors in rheumatoid arthritis

“…It is possible that activation through an endogenous TLR ligand, such as heat-shock proteins (HSPs) (17,47), may predispose the macrophages to heightened activation by subsequent exposure to microbial TLR ligands (48,49). Alternatively, it is also feasible that prior in vivo exposure to potential endogenous TLR-2 or TLR-4 ligands may have induced tolerance to repeat stimulation (50,51), partially reducing the response expected for the level of TLR-2 or TLR-4 expression in some RA patients, and possibly accounting for the lack of association between TLR expression and response to TLR ligand in RA patients.…”

Heat-shock proteins induce T-cell regulation of chronic inflammation

“…25 26 Moreover, HSP60 induced TLR signalling has been shown to be dependent on endocytosis, in contrast with LPS, which signals at the cell surface. 27 Although extensive data support a role for HSP in the activation of both innate and adaptive immune cells (fig 1), it is apparent from the above mentioned data that knowledge of the origin and purity of the HSP proteins used in experiments is important.…”

Deletion of Apoptosis Inhibitor of Macrophage (AIM)/CD5L Attenuates the Inflammatory Response and Infarct Size in Acute Myocardial Infarction

“…TLR‐4 is activated by the recognition of not only pathogen‐associated molecular patterns, such as bacterial lipopolysaccharide (LPS),17 but also endogenous host‐derived ligands including heat shock protein 60 (HSP60), high‐mobility group box 1 (HMGB‐1), extradomain degradation products of the extracellular matrix (ECM), and free fatty acids (FFA) in innate immunity 14, 15, 16, 18, 19, 20, 21, 22…”