The anti-inflammatory mechanisms of Hsp70

Abstract

Immune responses to heat shock proteins (Hsp) develop in virtually all inflammatory diseases; however, the significance of such responses is only now becoming clear. In experimental disease models, Hsp administration can prevent or arrest inflammatory damage, and in initial clinical trials in patients with chronic inflammatory diseases, Hsp peptides have been shown to promote the production of anti-inflammatory cytokines, indicating immunoregulatory potential of Hsp. Therefore, the presence of immune responses to Hsp in inflammatory diseases can be seen as an attempt of the immune system to correct the inflammatory condition. Hsp70 can modulate inflammatory responses in models of arthritis, colitis and graft rejection, and the mechanisms underlying this effect are now being elucidated. Incubation with microbial Hsp70 was seen to induce tolerogenic dendritic cells (DCs) and to promote a suppressive phenotype in myeloid-derived suppressor cells and monocytes. These DC could induce regulatory T cells (Tregs), independently of the antigens they presented. Some Hsp70 family members are associated with autophagy, leading to a preferential uploading of Hsp70 peptides in MHC class II molecules of stressed cells. Henceforth, conserved Hsp70 peptides may be presented in these situations and constitute targets of Tregs, contributing to downregulation of inflammation. Finally, an interfering effect in multiple intracellular inflammatory signaling pathways is also known for Hsp70. Altogether it seems attractive to use Hsp70, or its derivative peptides, for modulation of inflammation. This is a physiological immunotherapy approach, without the immediate necessity of defining disease-specific auto-antigens. In this article, we present the evidence on anti-inflammatory effects of Hsp70 and discuss the need for experiments that will be crucial for the further exploration of the immunosuppressive potential of this protein.

Keywords: Hsp70; adaptive immunity; immunomodulation; innate immunity; stress proteins.

FIGURE 1

Hsp70 can interact directly with innate immune cells. (A) A possible mechanism of the Hsp70 action is its interaction with dendritic cells (DCs), myeloid-derived suppressor cells (MDSCs), and monocytes. Hsp70 would bind to endocytic receptors, and be endocytosed, gaining access to routes of antigen presentation, modulating the cell phenotype toward a tolerogenic one, leading to the production of the anti-inflammatory cytokine IL-10 and consequently to immunosuppression. In DCs, Hsp70 downregulates CD86 and MHC class II expression, and inhibits TNF-α production. Also, Hsp70 can inhibit IFN-γ by monocytes. (B) Upon binding to an endocytic, Hsp70 signals through TLR2, resulting in MyD88 activation. The subsequent phosphorylation of ERK can trigger the activation of an undetermined transcription factor that will bind the il-10 gene promoter leading to IL-10 production.

FIGURE 2

Hsp-specific immunoregulation in the healthy and aged immune system. Self-Hsp-specific T cells reside in the circulation after escape from central tolerance in the thymus. Since Hsp are highly conserved, these self-Hsp-specific T cells can cross-recognize bacterial-Hsp. This T cell population can be expanded after exposure to bacterial-Hsp at mucosal surfaces like the gut or during infection. At mucosal surfaces, these T cells will be directed toward a regulatory phenotype through mechanisms of mucosal tolerance. In addition, Treg induction and maintenance will be promoted by stress-induced Hsp expression in peripheral tissues, because up-regulation of self-Hsp and presentation of Hsp peptides by MHC class II can occur in the absence of co-stimulation. Treg induction will be enhanced by IL-10 produced in response to stress. Furthermore, self-Hsp peptides can function as altered peptide ligands for bacterial-Hsp-specific T cells. During inflammation, Hsp will be induced and presented on professional APCs at the inflammatory site, leading to full activation of Hsp-specific Treg and local dampening ongoing inflammation. In the aged immune system, stress-induced Hsp expression is decreased. Therefore, reduced Hsp inducibility will probably influence both the induction of Hsp-specific Treg in the periphery and their activation during inflammation. Ultimately, this could result in reduced Treg numbers and function.