Il36g, also known as interleukin 36 gamma, is a cytokine that plays a role in inflammatory responses and immune-related processes. It is involved in pathways such as the IL-23/IL-17 axis which is critical in psoriasis pathology [5]. Genetic models can help in understanding its function and how it contributes to disease development.

In psoriasis, studies have found multiple associations related to Il36g. A SNP in PCSK9, a psoriasis-susceptibility locus, shows an inverse relationship with Il36G expression, with PCSK9 expression highest in basal and early spinous layer keratinocytes and Il36G expression highest in granular layer keratinocytes [1]. In cancer cachexia, IL36G-producing neutrophil-like monocytes emerge in the advanced cancer milieu and promote skeletal muscle loss, and genetic inhibition of IL36G-mediated signaling attenuates muscle loss and rescues cachexia phenotypes [2]. In psoriasis, SFRP2+ fibroblasts can activate Il36G in keratinocytes, further amplifying inflammatory responses [3]. Also, the IL36G rs7584409 variant shows a protective effect in psoriasis in general, but in patients with psoriasis, the G allele is associated with moderate-to-severe disease and psoriatic arthritis [4]. Polymorphisms in the Il36G gene are associated with plaque psoriasis, potentially affecting the functionality of the IL-36γ cytokine [5]. In hidradenitis suppurativa compared to psoriasis, there are differences in cytokine expression, with IL36G expressed by HS epidermis keratinocytes [6]. In depression, the IL-36G-IL-1RL2 axis is identified as a potential target, as neutrophils release IL-36G when stimulated with vasopressin, leading to neuroinflammation [7]. In psoriasis, NETs drive inflammatory responses through activation of epidermal TLR4/IL-36R crosstalk, and targeting NETs decreases IL-36G expression [8].

In conclusion, Il36g is significantly involved in inflammatory-related diseases such as psoriasis, cancer cachexia, and potentially depression. The study of Il36g using genetic models, especially in the context of these diseases, has provided insights into its role in promoting inflammation, muscle loss, and other disease-associated phenotypes, highlighting its potential as a therapeutic target.

References:

1. Merleev, Alexander, Ji-Xu, Antonio, Toussi, Atrin, Gudjonsson, Johann E, Maverakis, Emanual. 2022. Proprotein convertase subtilisin/kexin type 9 is a psoriasis-susceptibility locus that is negatively related to IL36G. In JCI insight, 7, . doi:10.1172/jci.insight.141193. https://pubmed.ncbi.nlm.nih.gov/35862195/

2. Hayashi, Yoshihiro, Kamimura-Aoyagi, Yasushige, Nishikawa, Sayuri, Harada, Yuka, Harada, Hironori. 2024. IL36G-producing neutrophil-like monocytes promote cachexia in cancer. In Nature communications, 15, 7662. doi:10.1038/s41467-024-51873-x. https://pubmed.ncbi.nlm.nih.gov/39266531/

3. Ma, Feiyang, Plazyo, Olesya, Billi, Allison C, Modlin, Robert L, Gudjonsson, Johann E. 2023. Single cell and spatial sequencing define processes by which keratinocytes and fibroblasts amplify inflammatory responses in psoriasis. In Nature communications, 14, 3455. doi:10.1038/s41467-023-39020-4. https://pubmed.ncbi.nlm.nih.gov/37308489/

4. Moreira, Cássio Rafael, de Alcântara, Camila Cataldi, Flauzino, Tamires, Reiche, Edna Maria Vissoci, Simão, Andréa Name Colado. 2023. IL36G genetic variant is independently associated with susceptibility, severity and joint involvement in psoriasis. In Molecular immunology, 159, 69-75. doi:10.1016/j.molimm.2023.05.010. https://pubmed.ncbi.nlm.nih.gov/37285630/

5. Traks, Tanel, Keermann, Maris, Prans, Ele, Kõks, Sulev, Kingo, Külli. 2019. Polymorphisms in IL36G gene are associated with plaque psoriasis. In BMC medical genetics, 20, 10. doi:10.1186/s12881-018-0742-2. https://pubmed.ncbi.nlm.nih.gov/30634937/

6. Kim, Jaehwan, Lee, Jongmi, Li, Xuan, Lowes, Michelle A, Krueger, James G. 2023. Single-cell transcriptomics suggest distinct upstream drivers of IL-17A/F in hidradenitis versus psoriasis. In The Journal of allergy and clinical immunology, 152, 656-666. doi:10.1016/j.jaci.2023.05.012. https://pubmed.ncbi.nlm.nih.gov/37271319/

7. Mou, Rong, Ma, Junkai, Ju, Xuan, Feng, Ye, Lu, Xinjiang. 2024. Vasopressin drives aberrant myeloid differentiation of hematopoietic stem cells, contributing to depression in mice. In Cell stem cell, 31, 1794-1812.e10. doi:10.1016/j.stem.2024.09.018. https://pubmed.ncbi.nlm.nih.gov/39442524/

8. Shao, Shuai, Fang, Hui, Dang, Erle, Gudjonsson, Johann E, Wang, Gang. 2019. Neutrophil Extracellular Traps Promote Inflammatory Responses in Psoriasis via Activating Epidermal TLR4/IL-36R Crosstalk. In Frontiers in immunology, 10, 746. doi:10.3389/fimmu.2019.00746. https://pubmed.ncbi.nlm.nih.gov/31024570/