Contribution of fibroblasts to tunnel formation and inflammation in hidradenitis suppurativa/ acne inversa

Abstract

The precise pathogenic mechanisms in the development, persistence and worsening of hidradenitis suppurativa (HS) remain ill-defined. This chronic inflammatory dermatosis displays a strong Th1 and Th17 inflammatory signature with elevated levels of TNF-α, IL-1β, IL-17 and IFNγ in lesional and perilesional tissue. HS significantly differs to other chronic inflammatory dermatoses due to the development of hypertrophic scarring and dermal tunnels. The development of scarring and tunnels suggests that fibroblastic stromal cells (including myofibroblasts, fibroblasts, pericytes etc) may be involved in the development and progression of disease. Heterogeneous populations of fibroblasts have been identified in other inflammatory disorders and malignancy which contribute to inflammation and present novel therapeutic targets for fibrotic disorders. Findings in HS are consistent with these fibroblast subpopulations and may contribute to tunnel formation, aggressive squamous cell carcinoma and the phenotypic presentation of familial HS variants. We describe the existing knowledge regarding these mechanistic pathways and methods to confirm their involvement in the pathogenesis of HS. K E Y W O R D S acne inversa, fibroblasts, hidradenitis suppurativa, pathogenesis, scarring | 887 FREW Et al.

Beyond antibodies: B cells in Hidradenitis Suppurativa: Bystanders, contributors or therapeutic targets?

“…CXCL9 and CXCL13 are produced by macrophages in human tissues, [33] although cutaneous T cells stimulated by DC's can also produce CXCL13 leading to CXCR5 dependent B‐cell migration into tissues [34] . Fibroblast stimulation by keratinocyte‐expressed cytokines and chemokines [35,36] is mediated via interferon signalling, [15] which is a component of pathogenesis in familial and spontaneous forms of HS [24,37] . These findings align with our previous discussion regarding fibroblasts and their role in HS‐associated inflammation [35] .…”

“…Fibroblast stimulation by keratinocyte‐expressed cytokines and chemokines [35,36] is mediated via interferon signalling, [15] which is a component of pathogenesis in familial and spontaneous forms of HS [24,37] . These findings align with our previous discussion regarding fibroblasts and their role in HS‐associated inflammation [35] . It also suggests that effector and antibody producing B cells may be recruited to lesional tissues via cytokines and chemokines derived from keratinocytes, fibroblasts, T cells and macrophages.…”

“…ASCA antibodies in IBD are strongly associated with the development of fibrosis and fistulae [49] . Exploration of similar associations in patients with HS may lead to predictive biomarkers for future fibrosis or tunnel formation, [35] although B cells may also have anti‐inflammatory activities in HS similar to their role in psoriasis [51,52] …”

Integrating complement into the molecular pathogenesis of Hidradenitis Suppurativa

“…[17] Given the dual expression of C5aR1 and C5aR2 on dermal fibroblasts and mast cells, [29] complement dysregulation may also contribute to the activation of fibroblasts. [30] Mast cell activity in psoriasis and atopic dermatitis (with which HS shares some immunological similarities) also demonstrates increased mast cell infiltrates, which produce IL-22, a potent T-cell activating/ recruiting cytokine. [31] Mast cell infiltrates are proportional to the disease severity and lead to B cell activation and proliferation consistent with the findings of CD19 + B cells in HS lesional tissues.…”

Role of the Complement Pathway in Inflammatory Skin Diseases: A Focus on Hidradenitis Suppurativa

“…Although the intertriginous areas are rich in apocrine glands (Hoffman et al, 2017;Vossen et al, 2018), eccrine gland transcriptomic signatures are also dysregulated in HS (Coates et al, 2019). Additional dermal factors, such as aberrant fibroblast responses, may contribute to the inflammatory sequelae of HS (Frew et al, 2019), including dermal tunnels, persistent suppuration, fibrosis, and systemic inflammation. The development of biofilms on epithelialized tunnels may explain HS flares.…”