IL-38 Aggravates Atopic Dermatitis via Facilitating Migration of Langerhans cells

Yue, Chengcheng; Hu, Yawen; Yu, Jiadong; Zhou, Hong; Zhou, Pei; Hu, Jing; Wang, Xiaoyan; Gu, Linna; Li, Ya; Feng, Yuting; Zeng, Fanlian; Zhao, Fulei; Li, Guolin; Zhao, Qixiang; Zhang, Chen; Zheng, Huaping; Wu, Wenling; Cui, Xinai; Huang, Nongyu; Wang, Zhen; Cui, Kaijun; Li, Jiong

doi:10.7150/ijbs.93843

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Int J Biol Sci 2024; 20(8):3094-3112. doi:10.7150/ijbs.93843 This issue Cite

Research Paper

IL-38 Aggravates Atopic Dermatitis via Facilitating Migration of Langerhans cells

Chengcheng Yue^1,†, Yawen Hu^1,†, Jiadong Yu^1,†, Hong Zhou^1,†, Pei Zhou¹, Jing Hu¹, Xiaoyan Wang¹, Linna Gu¹, Ya Li¹, Yuting Feng¹, Fanlian Zeng¹, Fulei Zhao¹, Guolin Li¹, Qixiang Zhao¹, Chen Zhang¹, Huaping Zheng¹, Wenling Wu¹, Xinai Cui⁴, Nongyu Huang¹, Zhen Wang^1,2, Kaijun Cui³, Jiong Li^1✉

1. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, 1 Keyuan 4th Road, Gaopeng Street, Chengdu, Sichuan 610041, China.
2. Department of Liver Surgery & Liver Transplantation, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, 37 Guo Xue Road, Chengdu, Sichuan 610041, China.
3. Department of Cardiology, West China Hospital, Sichuan University, 37 Guoxue Road, Chengdu, Sichuan 610041, China.
4. CDUTCM-KEELE Joint Health and Medical Sciences Institute, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
^†These authors contributed equally.

Citation:

Yue C, Hu Y, Yu J, Zhou H, Zhou P, Hu J, Wang X, Gu L, Li Y, Feng Y, Zeng F, Zhao F, Li G, Zhao Q, Zhang C, Zheng H, Wu W, Cui X, Huang N, Wang Z, Cui K, Li J. IL-38 Aggravates Atopic Dermatitis via Facilitating Migration of Langerhans cells. Int J Biol Sci 2024; 20(8):3094-3112. doi:10.7150/ijbs.93843. https://www.ijbs.com/v20p3094.htm

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Abstract

Atopic dermatitis (AD) is a common inflammation skin disease that involves dysregulated interplay between immune cells and keratinocytes. Interleukin-38 (IL-38), a poorly characterized IL-1 family cytokine, its role and mechanism in the pathogenesis of AD is elusive. Here, we show that IL-38 is mainly secreted by epidermal keratinocytes and highly expressed in the skin and downregulated in AD lesions. We generated IL-38 keratinocyte-specific knockout mice (K14^Cre/+-IL-38^f/f) and induced AD models by 2,4-dinitrofluorobenzene (DNFB). Unexpectedly, after treatment with DNFB, K14^Cre/+-IL-38^f/f mice were less susceptible to cutaneous inflammation of AD. Moreover, keratinocyte-specific deletion of IL-38 suppressed the migration of Langerhans cells (LCs) into lymph nodes which results in disturbed differentiation of CD4⁺T cells and decreased the infiltration of immune cells into AD lesions. LCs are a type of dendritic cell that reside specifically in the epidermis and regulate immune responses. We developed LC-like cells in vitro from mouse bone marrow (BM) and treated with recombined IL-38. The results show that IL-38 depended on IL-36R, activated the phosphorylated expression of IRAK4 and NF-κB P65 and upregulated the expression of CCR7 to promoting the migration of LCs, nevertheless, the upregulation disappeared with the addition of IL-36 receptor antagonist (IL-36RA), IRAK4 or NF-κB P65 inhibitor. Furthermore, after treatment with IRAK4 inhibitors, the experimental AD phenotypes were alleviated and so IRAK4 is considered a promising target for the treatment of inflammatory diseases. Overall, our findings indicated a potential pathway that IL-38 depends on IL-36R, leading to LCs migration to promote AD by upregulating CCR7 via IRAK4/NF-κB and implied the prevention and treatment of AD, supporting potential clinical utilization of IRAK4 inhibitors in AD treatment.

Keywords: Atopic dermatitis, Interleukin-38, Langerhans cells migrating

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APA

Yue, C., Hu, Y., Yu, J., Zhou, H., Zhou, P., Hu, J., Wang, X., Gu, L., Li, Y., Feng, Y., Zeng, F., Zhao, F., Li, G., Zhao, Q., Zhang, C., Zheng, H., Wu, W., Cui, X., Huang, N., Wang, Z., Cui, K., Li, J. (2024). IL-38 Aggravates Atopic Dermatitis via Facilitating Migration of Langerhans cells. International Journal of Biological Sciences, 20(8), 3094-3112. https://doi.org/10.7150/ijbs.93843.

ACS

Yue, C.; Hu, Y.; Yu, J.; Zhou, H.; Zhou, P.; Hu, J.; Wang, X.; Gu, L.; Li, Y.; Feng, Y.; Zeng, F.; Zhao, F.; Li, G.; Zhao, Q.; Zhang, C.; Zheng, H.; Wu, W.; Cui, X.; Huang, N.; Wang, Z.; Cui, K.; Li, J. IL-38 Aggravates Atopic Dermatitis via Facilitating Migration of Langerhans cells. Int. J. Biol. Sci. 2024, 20 (8), 3094-3112. DOI: 10.7150/ijbs.93843.

NLM

CSE

Yue C, Hu Y, Yu J, Zhou H, Zhou P, Hu J, Wang X, Gu L, Li Y, Feng Y, Zeng F, Zhao F, Li G, Zhao Q, Zhang C, Zheng H, Wu W, Cui X, Huang N, Wang Z, Cui K, Li J. 2024. IL-38 Aggravates Atopic Dermatitis via Facilitating Migration of Langerhans cells. Int J Biol Sci. 20(8):3094-3112.

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