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Commentary: IFN-k is a rheostat for development of psoriasiform inflammation

blog_image_-_commentary_-_pincelli
_pincelli_carlo
Carlo Pincelli, MD, PhD
University of Modena & Reggio Emiliana
Modena, Italy

PUBLICATION

IFN-k is a rheostat for development of psoriasiform inflammation. Gharaee-Kermani M, Estadt SN, Tsoi LC, Wolf-Fortune SJ, Liu J, Xing X, Theros J, Reed TJ, Lowe L, Gruszka D, Ward NL, Gudjonsson JE, Kahlenberg JM. J Invest Dermatol. 2022 Jan;142(1):155-165.e3. doi: 10.1016/j.jid.2021.05.029. Epub 2021 Aug 5. PMID: 34364883; PMCID: PMC8688309.

Why this article was chosen

This innovative research connects insights into immunopathogenesis with genetics and modes of action of treatments. More specifically, evidence is provided for keratinocytes-derived IFN-k as an early event relevant as a treatment target.

Commentary

“Rheostat” is a word coined in the nineteenth century to describe a device that regulates and adjusts the magnitude of electric current. Gharaee-Kermani et al. has recently used this term to define the newly identified role for interferon-k (IFN-k) in psoriatic lesions. They first demonstrated that IFN-regulated genes are increased in lesional and, to a lesser extent, in non-lesional psoriatic skin. They also showed that these genes correlate with psoriasis-associated cytokines, such as IL23 and IL17A. Notably, IFN-k is expressed in the psoriatic epidermis. To shed more light on the role of IFNs in the pathogenesis of psoriasis and to validate their hypothesis of IFN-k acting as a “rheostat” for psoriatic inflammation, Gharaee-Kermani and co-workers stimulated wild-type mice (WT), mice overexpressing IFN-k in the epidermis (Ifnk -TG), and mice lacking IFN-k (Ifnk-KO) with imiquimod (IMQ) to induce psoriasiform inflammation. Whereas Ifnk-KO mice developed only a mild inflammatory phenotype, ear thickness was significantly increased in Ifnk-TG compared to WT mice. The psoriatic phenotype amplified by IFN-k was further confirmed by the histopathologic features of psoriasis and the higher number of dendritic cells (DC), neutrophils, and macrophages in Ifnk-TG mice than in the other groups. Both IFN-regulated genes and genes associated with IL-17 response in psoriatic skin were significantly increased in mice that overexpressed IFN-k at the epidermal level. Finally, T-cells were more numerous in Ifnk-TG than in Ifnk-KO and WT mice. However, it should be noted that mice overexpressing IFN-k at baseline did not display a psoriasiform phenotype, suggesting that the cytokine alone is not sufficient to induce the disease. Because deletion of IFN-k attenuates the IMQ-induced inflammation, the authors concluded that targeting IFN-k may be an early treatment for psoriasis.

As pointed out by Garzorz-Stark and Kilian Eyerich1 in the Commentary related to the present article, in psoriatic skin, there are two immune axes involving IFNs: pDC-derived IFN-a and keratinocytes-derived IFN-k, both leading to type 1 (Th1, IL-12, and IFN-g) and type 3 (IL-23, Th17, IL-17) immune responses. This also implies an active role for keratinocytes in psoriasis.
  1. Garzorz-Stark N, Eyerich K. IFNs: Sentinels shaping distinct immune responses in skin. J Invest Dermatol (2022) 142: 14-15.

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