Il17d is a member of the interleukin-17 family of cytokines. The functions of this family are diverse, involving host defense, autoimmune disease development, and inflammation [1,3,4,6]. However, the functions of Il17d were initially elusive [1]. It is now known to be involved in regulating inflammatory responses and tissue homeostasis through specific signaling pathways.

In Il17d-/-mice, which are a gene knockout (KO) mouse model, there is increased susceptibility to acute colitis, bacterial infection, and experimentally induced colon cancer. Il17d deficiency impairs IL-22 production by group 3 innate lymphoid cells (ILC3s) and reduces expression of IL-22-dependent antimicrobial peptides in the colon, leading to changes in microbial composition and dysbiosis. Protein purification studies show that IL-17D binds to CD93, a glycoprotein expressed on mature ILC3s, and mice lacking Cd93 in ILC3s also exhibit impaired IL-22 production and aggravated colonic inflammation, indicating an IL-17D-CD93 axis regulating ILC3 function to maintain intestinal homeostasis [5]. In keratinocytes, IL-17D can induce the inhibition of DDX5 expression through the CD93-p38 MAPK-AKT-SMAD2/3 signaling pathway. This leads to pre-messenger RNA splicing events that selectively amplify IL-36R-mediated inflammatory responses and cutaneous inflammation, as seen in atopic dermatitis and psoriasis [2].

In conclusion, Il17d plays crucial roles in maintaining intestinal homeostasis by regulating ILC3 function and in modulating inflammation in keratinocytes during inflammatory skin diseases. The use of Il17d KO mouse models has been instrumental in uncovering these functions, providing insights into the pathogenesis of colonic diseases and inflammatory skin conditions such as atopic dermatitis and psoriasis.

References:

1. Iwakura, Yoichiro, Ishigame, Harumichi, Saijo, Shinobu, Nakae, Susumu. . Functional specialization of interleukin-17 family members. In Immunity, 34, 149-62. doi:10.1016/j.immuni.2011.02.012. https://pubmed.ncbi.nlm.nih.gov/21349428/

2. Ni, Xinhui, Xu, Yi, Wang, Wang, Dong, Chen, Lai, Yuping. 2022. IL-17D-induced inhibition of DDX5 expression in keratinocytes amplifies IL-36R-mediated skin inflammation. In Nature immunology, 23, 1577-1587. doi:10.1038/s41590-022-01339-3. https://pubmed.ncbi.nlm.nih.gov/36271146/

3. Brembilla, Nicolo Costantino, Senra, Luisa, Boehncke, Wolf-Henning. 2018. The IL-17 Family of Cytokines in Psoriasis: IL-17A and Beyond. In Frontiers in immunology, 9, 1682. doi:10.3389/fimmu.2018.01682. https://pubmed.ncbi.nlm.nih.gov/30127781/

4. Brembilla, Nicolo Costantino, Boehncke, Wolf-Henning. 2023. Revisiting the interleukin 17 family of cytokines in psoriasis: pathogenesis and potential targets for innovative therapies. In Frontiers in immunology, 14, 1186455. doi:10.3389/fimmu.2023.1186455. https://pubmed.ncbi.nlm.nih.gov/37283755/

5. Huang, Jinling, Lee, Hae-Youn, Zhao, Xiaohong, Wang, Xiaohu, Dong, Chen. . Interleukin-17D regulates group 3 innate lymphoid cell function through its receptor CD93. In Immunity, 54, 673-686.e4. doi:10.1016/j.immuni.2021.03.018. https://pubmed.ncbi.nlm.nih.gov/33852831/

6. Taams, Leonie S, Steel, Kathryn J A, Srenathan, Ushani, Burns, Lachrissa A, Kirkham, Bruce W. . IL-17 in the immunopathogenesis of spondyloarthritis. In Nature reviews. Rheumatology, 14, 453-466. doi:10.1038/s41584-018-0044-2. https://pubmed.ncbi.nlm.nih.gov/30006601/