Heat Shock Proteins Alterations in Rheumatoid Arthritis

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory and autoimmune disease characterized by the attack of the immune system on the body's healthy joint lining and degeneration of articular structures. This disease involves an increased release of inflammatory mediators in the affected joint that sensitize sensory neurons and create a positive feedback loop to further enhance their release. Among these mediators, the cytokines and neuropeptides are responsible for the crippling pain and the persistent neurogenic inflammation associated with RA. More importantly, specific proteins released either centrally or peripherally have been shown to play opposing roles in the pathogenesis of this disease: an inflammatory role that mediates and increases the severity of inflammatory response and/or an anti-inflammatory and protective role that modulates the process of inflammation. In this review, we will shed light on the neuroimmune function of different members of the heat shock protein (HSPs) family and the complex manifold actions that they exert during the course of RA. Specifically, we will focus our discussion on the duality in the mechanism of action of Hsp27, Hsp60, Hsp70, and Hsp90.

Keywords: HSP therapy; heat shock proteins; inflammation; neurogenic inflammation; rheumatoid arthritis; vaccine.

Figure 1

Neurogenic inflammation mechanism of action in Rheumatoid arthritis (RA). The mechanism of action of neuroinflammation in RA consists of: (1) activation and invasion of inflammatory synovial cells (T cells, B cells, macrophages, plasma cells, and dendritic cells) leading to peripheral sensitization and local inflammatory reaction that (2) sensitizes peripheral small diameter fibers (A, B, and C fibers), hence generating dorsal root reflexes. (3) Peripheral nerve endings and the central nerve endings originating from the dorsal root ganglion release substance P (SP), calcitonin gene-related peptide (CGRP), and glutamate that peripherally act on post-capillary venules, rendering them leaky and resulting in plasma extravasation and vasodilation, while, centrally, they trigger neurogenic inflammation. Therefore, this integrated inflammatory network (4) enhances the release of inflammatory cytokines nerve growth factor beta (NGF-β), interleukin (IL)-1, IL-6, IL-17, and tumor necrosis factor alpha (TNF-α) (as indicated by the red arrows) and (5) activates microglial cells in the dorsal horn of the spinal cord.

Figure 2

Molecular mechanisms of Hsp27 in neurogenic inflammation and in pathophysiology of RA. Hsp27 enhances the production of the proinflammatory IL-8 and decreases the secretion of anti-inflammatory transforming growth factor β1 (TGF-β1), leading to neurogenic inflammation. Additionally, Hsp27 increases the secretion of IL-1 and TNF, which activate the p38 mitogen-activated protein kinase (MAPK) pathway, leading to synovial inflammation. α-crystallin and HSPB8 activate toll-like receptor 4 (TLR4), thus enhancing dendritic cell maturation and proinflammatory cytokine secretion (IL-6 and TNF-α), leading to RA progression. Exogenous Hsp27 (eHsp27) enhances the production of inhibitory mediators thrombospodin-1 and IL10, leading to the decrease in the differentiation of monocytes to dendritic cells, ensuring anti-inflammatory properties. HSB1 inhibits the activation the pf nuclear factor kappa B (NF-κB) pathway and consequently decreases the secretion of TNF-α (as indicated by the red arrow) by microglial cells, thus playing a pivotal role in dampening neurogenic inflammation.

Figure 3

Molecular mechanisms of Hsp60, 70, and 90 in pathophysiology of RA. Preimmunization with naked DNA of mycobacterial Hsp65 (MtHsp65) or MtHsp65 leads to recognition of Hsp65 and cross-reactive recognition of self-Hsp60 (sHsp60) epitopes by CD4+ and CD8+T cells, which confer protection in RA through a T-cell-mediated protective immune response. Intracellular Hsp60 and administration of arthritis-related Hsp60 T-cell epitope (AHsp60) can dampen RA-related inflammation by T-regulatory cells (Treg)-mediated stimulation of secretion of anti-inflammatory cytokines TGF-β, IL-4, and IL-10. Hsp70 increases proinflammation and apoptosis by upregulating TNF-α and inhibiting pro-survival Akt signaling pathways, respectively. Hsp70 and Hsp90 DNA vaccination conferred anti-inflammatory protection via increase in anti-inflammatory cytokines TGF-β1 and IL-10. Extracellular Hsp70 (eHsp70) downregulates inflammatory processes by inhibiting nuclear translocation of NF-κB (p65/50) and transcription of proinflammatory cytokines MCP-1, IL-6, and IL-8 (green arrow indicates a decrease in gene expression). Target inhibition of Hsp90 by EC144 promotes the diminishment of CD4+T-cell-mediated immune response.