Expanding strategies to resolve psoriasis-like inflammation: Non-canonical NF-κB signaling controls IL-23 production in dendritic cells

Inflammation is a crucial process employed by the immune system to control pathogens and other invading stimuli. After clearance, inflammation is resolved and controlled by multiple mechanisms to prevent unwanted and excessive inflammatory processes. In cases of failure of these control mechanisms, chronic inflammatory diseases can arise. A classic example of a chronic inflammatory disease is psoriasis, which clinically manifests in the skin as scaly, erythematous lesions and affects approximately 2%–3% of people worldwide. 1 Armstrong A.W. Read C. Pathophysiology, Clinical Presentation, and Treatment of Psoriasis: A Review. Jama. 2020; 323: 1945-1960https://doi.org/10.1001/jama.2020.4006 Google Scholar In psoriasis, the interleukin (IL)-17/IL-23 axis has been shown to be a major signaling pathway in disease pathology, and multiple immunotherapies targeting this pathway have been developed. 2 Miossec P. Kolls J.K. Targeting IL-17 and TH17 cells in chronic inflammation. Nat. Rev. Drug Discov. 2012; 11: 763-776https://doi.org/10.1038/nrd3794 Google Scholar While immunotherapies have good clinical efficacy, they globally inhibit effector responses, making patients susceptible to opportunistic infections. 3 Penso L. Dray-Spira R. Weill A. Pina Vegas L. Zureik M. Sbidian E. Association Between Biologics Use and Risk of Serious Infection in Patients With Psoriasis. JAMA Dermatol. 2021; 157: 1056-1065https://doi.org/10.1001/jamadermatol.2021.2599 Google Scholar Hence, there would be great benefit in developing therapies aimed at reinstating immune homeostasis in the tissue. In a recent article published in Molecular Therapy, Xia et al. 4 Xia X. Zhu L. Xu M. Lei Z. Yu H. Li G. Wang X. Jia H. Yin Z. Huang F. Gao Y. ANKRD22 promotes resolution of psoriasiform skin inflammation by antagonizing NIK-mediated IL-23 production. Mol. Ther. 2024; https://doi.org/10.1016/j.ymthe.2024.03.007 Google Scholar highlight that this could be possible by targeting ANKRD22, an ankyrin repeat-containing protein family member. Using a mouse model of psoriasis, the authors show that ANKRD22 is lost in inflamed psoriatic skin and is able to bind nuclear factor κB (NF-κB)-inducing kinase (NIK) and target it for degradation, leading to downregulation of non-canonical NF-κB signaling and subsequent resolution of inflammation. This pathway specifically affects dendritic cells' (DCs') ability to produce IL-23, which in turn causes a decrease in IL-17A-producing T cells, thereby blocking the initiation and maintenance of the IL-17 inflammatory loop associated with psoriasis.