Keratinocyte-derived S100A9 modulates neutrophil infiltration and affects psoriasis-like skin and joint disease. Issue 10 (4th July 2022)

• Record Type: Journal Article
• Authors: Mellor, Liliana F; Gago-Lopez, Nuria; Bakiri, Latifa; Schmidt, Felix N; Busse, Björn; Rauber, Simon; Jimenez, Maria; Megías, Diego; Oterino-Sogo, Sergio; Sanchez-Prieto, Ricardo; Grivennikov, Sergei; Pu, Xinzhu; Oxford, Julia; Ramming, Andreas; Schett, Georg; Wagner, Erwin F
• Is Part Of: Annals of the rheumatic diseases. Volume 81:Issue 10(2022)
• Page Start: 1400
• Page End: 1408
• Publication Date: 2022-07-04
• Subjects: psoriatic arthritis -- cytokines -- inflammation; Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2022-222229
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : Objectives: S100A9, an alarmin that can form calprotectin (CP) heterodimers with S100A8, is mainly produced by keratinocytes and innate immune cells. The contribution of keratinocyte-derived S100A9 to psoriasis (Ps) and psoriatic arthritis (PsA) was evaluated using mouse models, and the potential usefulness of S100A9 as a Ps/PsA biomarker was assessed in patient samples. Methods: Conditional S100A9 mice were crossed with DKO* mice, an established psoriasis-like mouse model based on inducible epidermal deletion of c-Jun and JunB to achieve additional epidermal deletion of S100A9 (TKO* mice). Psoriatic skin and joint disease were evaluated in DKO* and TKO* by histology, microCT, RNA and proteomic analyses. Furthermore, S100A9 expression was analysed in skin, serum and synovial fluid samples of patients with Ps and PsA. Results: Compared with DKO* littermates, TKO* mice displayed enhanced skin disease severity, PsA incidence and neutrophil infiltration. Altered epidermal expression of selective pro-inflammatory genes and pathways, increased epidermal phosphorylation of STAT3 and higher circulating TNFα were observed in TKO* mice. In humans, synovial S100A9 levels were higher than the respective serum levels. Importantly, patients with PsA had significantly higher serum concentrations of S100A9, CP, VEGF, IL-6 and TNFα compared with patients with only Ps, but only S100A9 and CP could efficiently discriminate healthy individuals, patients with Ps and patients with PsA. Conclusions: Keratinocyte-derived S100A9 plays a regulatory role in psoriatic skin and joint disease. In humans, S100A9/CP is a promising marker that could help in identifying patients with Ps at risk of developing PsA.