Study: Inhibiting S100A9 Gene in Skin Cells Reduces Severity of Psoriasis, Psoriatic Arthritis

The severity of psoriasis (Ps) and psoriatic arthritis (PsA) can be reduced by inhibiting the S100A9 gene throughout the body, rather than locally on the skin, according to the results of a study led by MedUni Vienna in Austria.¹

“Our study is an important step toward the development of targeted therapeutic options in the form of drugs that act systemically rather than locally on the skin,” Erwin Wagner, PhD, from the department of dermatology and department of laboratory medicine at MedUni Vienna, said in a statment.¹

S100A9 is an alarmin that forms calprotectin (CP) heterodimers with S100A8 and is mainly produced by immune cells and keratinocytes.²

Triggers for Ps, which usually appear in adulthood, can include stress and ultraviolet radiation. However, individuals can also be genetically predisposed to developing the disease through S100A9 activation in skin and immune cells.¹

Previous research from the investigative team showed that the symptoms of Ps fade when the S100A9 gene is deactivated in all cells within the body. In recent preclinical experiments, investigators were able to see the influence of the skin and immune cells where S100A9 is produced have on disease severity.¹

Investigators crossed S100A9 mice with double knock out (DKO*) mice, which were an established Ps-like mouse model-based triple knock out (TKO*) mice, including inducible epidermal deletion of c-Jun and JunB to achieve the deletion of S100A9.²

Ps skin and joint disease were evaluated in DKO* and TKO* by histology, microCT, RNA, and protemic analyses. The S100A9 expression was also analyzed in the skin, serum, and synovial fluid samples of individuals with Ps and PsA.²

Investigators found that compared with the DKO* mice, the TKO* mice had increased neutrophil infiltration, PsA incidence, and skin disease severity. Additionally, investigators observed altered epidermal expression of selective pro-inflammatory genes and pathways, increased epidermal phosphorylation of STAT3, and higher circulating TNFα in the TKO* mice.²

In humans, the investigators found that synovial S100A9 levels were higher in the respective serum levels, with individuals with PsA having significantly higher serum concentrations of CP, S100A9, interleukin-6, TNFα, and VEGF.²

However, only CP and S100A9 could efficiently discriminate healthy individuals, participants with Ps, and those with PsA.²

“We now know that the inflammatory responses in psoriasis and psoriatic arthritis are enhanced when S100A9 is only inhibited in skin cells,” Wagner.¹

Investigators noted the S100A9 gene and CP could be promising markers that could help identify individuals with Ps who are at risk of developing PsA.²

The results indicated that drugs inhibiting S100A9 should be administered systemically in the form of drips or tablets.¹

This study, as reported by the investigators, is the first to use a new S100A9 floxed allele to help investigate the role of epidermal-derived S100A9 in vivo.²

References

1. Psoriasis: study lays foundation for new treatment strategy. News release. EurekAlert. July 6, 2022. Accessed November 7, 2022. https://www.eurekalert.org/news-releases/957986

2. Mellor LF, Gago-Lopez N, Bakiri L, et al. Keratinocyte-derived S100A9 modulates neutrophil infiltration and affects psoriasis-like skin and joint disease. Annals of the Rheumatic Diseases. 2022;81:1400-1408. doi:10.1136/annrheumdis-2022-222229