Heat Shock Protein 90 (Hsp90) and Hsp70 as Potential Therapeutic Targets in Autoimmune Skin Diseases

Abstract

Over a hundred different autoimmune diseases have been described to date, which can affect every organ in the body, including the largest one, the skin. In fact, up to one-fifth of the world’s population suffers from chronic, noninfectious inflammatory skin diseases, the development of which is significantly influenced by an autoimmune response. One of the hallmarks of autoimmune diseases is the loss of immune tolerance, which leads to the formation of autoreactive lymphocytes or autoantibodies and, consequently, to chronic inflammation and tissue damage. The treatment of autoimmune skin diseases mainly focuses on immunosuppression (using, e.g., corticosteroids) but almost never leads to the development of permanent mechanisms of immune tolerance. In addition, current therapies and their long-term administration may cause serious adverse effects. Hence, safer and more effective therapies that bring sustained balance between pro- and anti-inflammatory responses are still desired. Both intra- and extracellular heat shock proteins (Hsps), specifically well-characterized inducible Hsp90 and Hsp70 chaperones, have been highlighted as therapeutic targets for autoimmune diseases. This review presents preclinical data on the involvement of Hsp90 and Hsp70 in modulating the immune response, specifically in the context of the treatment of selected autoimmune skin diseases with emphasis on autoimmune bullous skin diseases and psoriasis.

Targeting heat shock proteins 90 and 70: A promising remedy for both autoimmune bullous diseases and COVID-19

“…However, several questions remain open. Independent reports on the role of Hsps90/70 in either AIBDs or COVID-19 do not ultimately imply a direct correlation between these stress proteins and both diseases, which is hampered by the fact that all information is limited to preclinical studies so far ( 9 , 18 , 19 ). In addition, the family of Hsps is large, and the interaction between each other and their client proteins is complex ( 1 ).…”

“…Several lines of evidence suggest that Hsp90 is involved as a notable pathophysiological factor in AIBDs including epidermolysis bullosa acquisita (EBA) and bullous pemphigoid. The antiinflammatory clinical and molecular effects of anti-Hsp90 treatment were mostly demonstrated in several EBA studies using corresponding in vivo mouse models, ex vivo human dermalepidermal separation cryosection experiments, and in vitro rodent and human cell culture assays (8,9). Hsp90 inhibitors, including 17-DMAG, 17-AAG, and TCBL-145, exhibited activity by potently affecting inflammatory disease pathways (e.g., suppression of effector T-cells, B-cells, and neutrophils; down-regulation of NF-kB activity; blunting of autoantibody, pro-inflammatory cytokine, and reactive oxygen species production; inhibition of matrix metalloproteinases; promotion of regulatory B cells) (10)(11)(12)(13).…”

“…Compared to Hsp90, the role of Hsp70 in AIBDs has been overall less studied ( 9 ). Two recent studies indicated that both extracellular Hsp70 and autoantibodies to Hsp70 display pro-inflammatory activities in the context of EBA development ( 16 , 17 ).…”

HSP90: A potential drug target in inflammatory skin diseases

“…HSP70 and HSP90 play important roles in maintaining cellular homoeostasis by facilitating protein folding. However, they differ in terms of their structure, function and regulation 4 . The aim of this review was to examine the clinical potential of targeting HSP90 for the treatment of inflammatory skin disease.…”

“…However, they differ in terms of their structure, function and regulation. 4 The aim of this review was to examine the clinical potential of targeting HSP90 for the treatment of inflammatory skin disease. We anticipate that this topic will be of significant interest to clinical dermatologists.…”