Targeting the NLRP3 inflammasome reduces inflammation in hidradenitis suppurativa skin.
Journal
The British journal of dermatology
ISSN: 1365-2133
Titre abrégé: Br J Dermatol
Pays: England
ID NLM: 0004041
Informations de publication
Date de publication:
15 09 2023
15 09 2023
Historique:
received:
21
12
2022
revised:
23
05
2023
accepted:
25
05
2023
medline:
18
9
2023
pubmed:
27
5
2023
entrez:
27
5
2023
Statut:
ppublish
Résumé
Treatment for the debilitating disease hidradenitis suppurativa (HS) is inadequate in many patients. Despite an incidence of approximately 1%, HS is often under-recognized and underdiagnosed, and is associated with a high morbidity and poor quality of life. To gain a better understanding of the pathogenesis of HS, in order to design new therapeutic strategies. We employed single-cell RNA sequencing to analyse gene expression in immune cells isolated from involved HS skin vs. healthy skin. Flow cytometry was used to quantify the absolute numbers of the main immune populations. The secretion of inflammatory mediators from skin explant cultures was measured using multiplex and enzyme-linked immunosorbent assays. Single-cell RNA sequencing analysis identified a significant enrichment in the frequency of plasma cells, T helper (Th) 17 cells and dendritic cell subsets in HS skin, and the immune transcriptome was distinct and more heterogeneous than healthy skin. Flow cytometry revealed significantly increased numbers of T cells, B cells, neutrophils, dermal macrophages and dendritic cells in HS skin. Genes and pathways associated with Th17 cells, interleukin (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. These data provide a rationale for targeting the NLRP3 inflammasome in HS using small-molecule inhibitors that are currently being tested for other indications.
Sections du résumé
BACKGROUND
Treatment for the debilitating disease hidradenitis suppurativa (HS) is inadequate in many patients. Despite an incidence of approximately 1%, HS is often under-recognized and underdiagnosed, and is associated with a high morbidity and poor quality of life.
OBJECTIVES
To gain a better understanding of the pathogenesis of HS, in order to design new therapeutic strategies.
METHODS
We employed single-cell RNA sequencing to analyse gene expression in immune cells isolated from involved HS skin vs. healthy skin. Flow cytometry was used to quantify the absolute numbers of the main immune populations. The secretion of inflammatory mediators from skin explant cultures was measured using multiplex and enzyme-linked immunosorbent assays.
RESULTS
Single-cell RNA sequencing analysis identified a significant enrichment in the frequency of plasma cells, T helper (Th) 17 cells and dendritic cell subsets in HS skin, and the immune transcriptome was distinct and more heterogeneous than healthy skin. Flow cytometry revealed significantly increased numbers of T cells, B cells, neutrophils, dermal macrophages and dendritic cells in HS skin. Genes and pathways associated with Th17 cells, interleukin (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 that are currently being tested for other indications.
Identifiants
pubmed: 37243544
pii: 7181042
doi: 10.1093/bjd/ljad184
doi:
Substances chimiques
Inflammasomes
0
NLR Family, Pyrin Domain-Containing 3 Protein
0
Inflammation Mediators
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
447-458Subventions
Organisme : Science Foundation Ireland (SFI)
Organisme : City of Dublin Skin and Cancer Hospital Charity (J.M.F.)
Organisme : Wellcome Trust and the Health Research Board
Commentaires et corrections
Type : CommentIn
Type : CommentIn
Informations de copyright
© The Author(s) 2023. Published by Oxford University Press on behalf of British Association of Dermatologists.
Déclaration de conflit d'intérêts
Conflicts of interest: R.H. has received honoraria from AbbVie, Janssen and UCB, and has acted as a subinvestigator in clinical trials for AbbVie and UCB. K.H.G.M. is the co-founder of and a shareholder in a startup biotechnology company involved in the development of anti-inflammatory therapeutics. B.K. has received grants and/or honoraria from AbbVie, Almirall, AstraZeneca, Biogen, Bristol Myers Squibb, Celgene, Janssen, Lilly, LEO Pharma, Merck, Moonlake, Novartis, Pfizer and UCB Pharma. J.M.F. has received honoraria from Novartis and Moonlake. M.R. is a former employee of AbbVie. B.M., C.M.S., A.Z., J.K., R.W.D., K.M.S., J.M., A.P., A.F., M.O’D., K.H., W.J.H. and D.C.W. declare no conflicts of interest.