Targeting the NLRP3 inflammasome reduces inflammation in hidradenitis suppurativa skin

Autor: Barry Moran, Conor M Smith, Alexandra Zabarowski, Mark Ryan, Jozsef Karman, Robert W Dunstan, Kathleen M Smith, Roisin Hambly, Jana Musilova, Andreea Petrasca, Aurelie Fabre, Margaret O’Donnell, Karsten Hokamp, Kingston H G Mills, William J Housley, Desmond C Winter, Brian Kirby, Jean M Fletcher
Rok vydání: 2023
Předmět:
Zdroj: British Journal of Dermatology.
ISSN: 1365-2133
0007-0963
Popis: Background Treatment for the debilitating disease hidradenitis suppurativa (HS) is inadequate in many patients. Despite an incidence of approximately 1%, HS is often underrecognized and underdiagnosed and is associated with a high morbidity and poor quality of life. Objectives A better understanding of its pathogenesis is required to design new therapeutic strategies. Methods In this study we employed single cell RNA sequencing to analyse gene expression in immune cells isolated from involved HS skin compared with healthy skin. Flow cytometry was used to quantify the absolute numbers of the main immune populations. Secretion of inflammatory mediators from skin explant cultures was measured using multiplex assays and ELISA. Results Single cell RNA sequencing analysis identified a significant enrichment in the frequency of plasma cells, Th17 cells and dendritic cell subsets in HS skin, and the immune transcriptome was distinct and much more heterogenous when compared with healthy skin. Flow cytometry revealed significantly increased numbers of T cells, B cells, neutrophils, dermal macrophages, and dendritic cells into involved HS skin. Genes and pathways associated with Th17 cells, IL-17, IL-1β, and the NLRP3 inflammasome were enhanced in HS skin, particularly in samples with a high inflammatory load. Inflammasome constituent genes principally mapped to Langerhans cells and a subpopulation of dendritic cells. The secretome of HS skin explants contained significantly increased concentrations of inflammatory mediators including IL-1β and IL-17A, and culture with an NLRP3 inflammasome inhibitor significantly reduced the secretion of these as well as other key mediators of inflammation. Conclusions These data provide a rationale for targeting the NLRP3 inflammasome in HS using small molecule inhibitors which are currently being tested for other indications.
Databáze: OpenAIRE
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