Aberrant inflammasome activation as a driving force of human autoimmune skin disease

Abstract

Autoimmune skin diseases are understood as conditions in which the adaptive immune system with autoantigen-specific T cells and autoantibody-producing B cells reacting against self-tissues plays a crucial pathogenic role. However, there is increasing evidence that inflammasomes, which are large multiprotein complexes that were first described 20 years ago, contribute to autoimmune disease progression. The inflammasome and its contribution to the bioactivation of interleukins IL-1β and IL-18 play an essential role in combating foreign pathogens or tissue damage, but may also act as a pathogenic driver of myriad chronic inflammatory diseases when dysfunctionally regulated. Inflammasomes containing the NOD-like receptor family members NLRP1 and NLRP3 as well as the AIM2-like receptor family member AIM2 have been increasingly investigated in inflammatory skin conditions. In addition to autoinflammatory diseases, which are often associated with skin involvement, the aberrant activation of the inflammasome has also been implied in autoimmune diseases that can either affect the skin besides other organs such as systemic lupus erythematosus and systemic sclerosis or are isolated to the skin in humans. The latter include, among others, the T-cell mediated disorders vitiligo, alopecia areata, lichen planus and cutaneous lupus erythematosus as well as the autoantibody-driven blistering skin disease bullous pemphigoid. Some diseases are characterized by both autoinflammatory and autoimmune responses such as the chronic inflammatory skin disease psoriasis. Further insights into inflammasome dysregulation and associated pathways as well as their role in forming adaptive immune responses in human autoimmune skin pathology could potentially offer a new field of therapeutic options in the future.

Triggers for the onset and recurrence of psoriasis: a review and update

“…Long double-stranded RNA (dsRNA) generated in the course of infections of positive-strand RNA viruses, e.g., Semliki Forest virus, can bind and activate NLRP1 inflammasome in human keratinocytes [ 82 ]. NLPR1 inflammasome has been implied in prompting the onset of psoriasis, either by increasing the susceptibility to psoriasis or by dysregulated release of pro-inflammatory cytokines including IL-1β and IL-18 [ 83 – 85 ]. Very similarly, NLRP1 has the capacity to sense bacterial pathogen exotoxin, such as exotoxin A secreted by Pseudomonas aeruginosa and diphtheria toxin by Corynebacterium diphtheriae , and induce cell death and IL-1β/ IL-18 secretion [ 86 ].…”