Human dermal fibroblast subpopulations and epithelial mesenchymal transition signals in hidradenitis suppurativa tunnels are normalized by spleen tyrosine kinase antagonism in vivo

• Published in: PloS one 2023-11, Vol.18 (11), p.e0282763-e0282763
• Main Authors: Flora, Akshay, Jepsen, Rebecca, Kozera, Emily K, Woods, Jane A, Cains, Geoffrey D, Radzieta, Michael, Jensen, Slade O, Malone, Matthew, Frew, John W
• Format: Article
• Language: English
• Subjects: B cells; Biology and Life Sciences; Biopsy; Care and treatment; CXCL12 protein; Cytokines; Diagnosis; Disease; E-cadherin; Extracellular matrix; Fibroblasts; Frizzled-related protein 1; Gene expression; Genes; Health aspects; Immunohistochemistry; Inflammation; Inflammatory diseases; Kinases; Medicine and Health Sciences; N-Cadherin; Pathogenesis; Phenols; Protein expression; Proteins; Research and Analysis Methods; RNA sequencing; Signatures; Skin diseases; Snail protein; Spleen; Stem cells; Subpopulations; Tissues; Tunnels; Tyrosine; Wound healing
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0282763

Hidradenitis Suppurativa is a chronic inflammatory disease of which the pathogenesis is incompletely understood. Dermal fibroblasts have been previously identified as a major source of inflammatory cytokines, however information pertaining to the characteristics of subpopulations of fibroblasts in HS remains unexplored. Using in silico-deconvolution of whole-tissue RNAseq, Nanostring gene expression panels and confirmatory immunohistochemistry we identified fibroblast subpopulations in HS tissue and their relationship to disease severity and lesion morphology. Gene signatures of SFRP2+ fibroblast subsets were increased in lesional tissue, with gene signatures of SFRP1+ fibroblast subsets decreased. SFRP2+ and CXCL12+ fibroblast numbers, measured by IHC, were increased in HS tissue, with greater numbers associated with epithelialized tunnels and Hurley Stage 3 disease. Pro-inflammatory CXCL12+ fibroblasts were also increased, with reductions in SFRP1+ fibroblasts compared to healthy controls. Evidence of Epithelial Mesenchymal Transition was seen via altered gene expression of SNAI2 and altered protein expression of ZEB1, TWIST1, Snail/Slug, E-Cadherin and N-Cadherin in HS lesional tissue. The greatest dysregulation of EMT associated proteins was seen in biopsies containing epithelialized tunnels. The use of the oral Spleen tyrosine Kinase inhibitor Fostamatinib significantly reduced expression of genes associated with chronic inflammation, fibroblast proliferation and migration suggesting a potential role for targeting fibroblast activity in HS.