HSP70 as Endogenous Stimulus of the Toll/Interleukin-1 Receptor Signal Pathway

TLDR

Human HSP70 activates innate immune cells, illustrating the expanding list of endogenous ligands that trigger the Toll/IL‑1 receptor pathway in line with the danger hypothesis. The study tested whether endogenous HSP70 activates the Toll/IL‑1 receptor pathway similarly to HSP60 and pathogen-derived patterns. HSP70 activates macrophages via MyD88/TRAF6, inducing IL‑12 and ELAM‑1 promoters, relocalizes MyD88, requires MyD88 for dendritic cell cytokine production, and TLR2 and TLR4 mediate responsiveness in 293T fibroblasts.

Abstract

Human heat-shock protein (HSP)70 activates innate immune cells and hence requires no additional adjuvants to render bound peptides immunogenic. Here we tested the assumption that endogenous HSP70 activates the Toll/IL-1 receptor signal pathway similar to HSP60 and pathogen-derived molecular patterns. We show that HSP70 induces interleukin-12 (IL-12) and endothelial cell-leukocyte adhesion molecule-1 (ELAM-1) promoters in macrophages and that this is controlled by MyD88 and TRAF6. Furthermore, HSP70 causes MyD88 relocalization and MyD88-deficient dendritic cells do not respond to HSP70 with proinflammatory cytokine production. Using the system of genetic complementation with Toll-like receptors (TLR) we found that TLR2 and TLR4 confer responsiveness to HSP70 in 293T fibroblasts. The expanding list of endogenous ligands able to activate the ancient Toll/IL-1 receptor signal pathway is in line with the "danger hypothesis" proposing that the innate immune system senses danger signals even if they originate from self.