Hsa_circ_0004287 inhibits macrophage-mediated inflammation in an N6-methyladenosine-dependent manner in atopic dermatitis and psoriasis

Lan Yang; Jinrong Fu; Xiao Han; Caiyan Zhang; Li Xia; Ronghui Zhu; Saihua Huang; Wenfeng Xiao; Hongmiao Yu; Yajing Gao; Qiuyan Liang; Wei Li; Yufeng Zhou

doi:10.1016/j.jaci.2021.11.024

Hsa_circ_0004287 inhibits macrophage-mediated inflammation in an N⁶-methyladenosine-dependent manner in atopic dermatitis and psoriasis

J Allergy Clin Immunol. 2022 Jun;149(6):2021-2033. doi: 10.1016/j.jaci.2021.11.024. Epub 2021 Dec 23.

Authors

Lan Yang¹, Jinrong Fu², Xiao Han¹, Caiyan Zhang³, Li Xia¹, Ronghui Zhu⁴, Saihua Huang¹, Wenfeng Xiao¹, Hongmiao Yu¹, Yajing Gao¹, Qiuyan Liang¹, Wei Li⁵, Yufeng Zhou⁶

Affiliations

¹ Institute of Pediatrics, Children's Hospital of Fudan University, National Children's Medical Center, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China; National Health Commission Key Laboratory of Neonatal Diseases, Fudan University, Shanghai, China.
² Institute of Pediatrics, Children's Hospital of Fudan University, National Children's Medical Center, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China; Department of General Medicine, Children's Hospital of Fudan University, Shanghai, China.
³ Institute of Pediatrics, Children's Hospital of Fudan University, National Children's Medical Center, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China; Department of Critical Care Medicine, Children's Hospital of Fudan University, Shanghai, China.
⁴ Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China.
⁵ Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China. Electronic address: liweiderma@fudan.edu.cn.
⁶ Institute of Pediatrics, Children's Hospital of Fudan University, National Children's Medical Center, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China; National Health Commission Key Laboratory of Neonatal Diseases, Fudan University, Shanghai, China. Electronic address: yfzhou1@fudan.edu.cn.

PMID: 34953789
DOI: 10.1016/j.jaci.2021.11.024

Abstract

Background: Circular RNA (circRNA) has been implicated in various diseases; however, its role in atopic dermatitis (AD) or psoriasis remains unclear.

Objective: We sought to determine the differential expression profiles of circRNAs in peripheral blood mononuclear cells between healthy controls and AD patients, and explore the mechanisms underlying the effects of circRNAs on the pathogenesis of AD.

Methods: The differential expression profiles of circRNAs were analyzed by circRNA microarray. In vitro function and mechanisms by which circRNAs regulate macrophage-mediated inflammation were detected by reverse transcription quantitative PCR, Western blot analysis, RNA stability assay, immunoprecipitation, ELISA, and methylated RNA immunoprecipitation assay. In vivo roles of circRNAs were determined in 2,4-dinitrochlorobenzene (DNCB)-induced dermatitis and imiquimod (IMQ)-induced psoriasis mouse model.

Results: We identified a functional unknown circRNA hsa_circ_0004287 from 88750 circRNAs, which was upregulated in peripheral blood mononuclear cells of both AD and psoriasis patients, and was mainly expressed by macrophages under inflammatory conditions. Hsa_circ_0004287 inhibited M1 macrophage activation in vitro, and macrophage-specific overexpression of hsa_circ_0004287 alleviated skin inflammation in both AD- and psoriasis-like mice. Mechanistically, hsa_circ_0004287 reduced the stability of its host gene metastasis associated lung adenocarcinoma transcript 1 (MALAT1) by competitively binding to IGF2BP3 with MALAT1 in an N⁶-methyladenosine (m⁶A)-dependent manner. Lower levels of MALAT1 promoted the ubiquitination degradation of S100A8/S100A9, thereby impeding p38/mitogen-activated protein kinase phosphorylation and macrophage-mediated inflammation.

Conclusion: hsa_circ_0004287 inhibits M1 macrophage activation in an m⁶A-dependent manner in AD and psoriasis, and may serve as a general therapeutic candidate for AD and psoriasis.

Keywords: Circular RNA; N(6)-methyladenosine; atopic dermatitis; macrophage activation; psoriasis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine / analogs & derivatives
Animals
Dermatitis, Atopic* / genetics
Humans
Inflammation / genetics
Leukocytes, Mononuclear / metabolism
Macrophages / metabolism
Mice
MicroRNAs* / metabolism
Psoriasis* / genetics
RNA, Circular / genetics
RNA, Long Noncoding*

Substances

MicroRNAs
RNA, Circular
RNA, Long Noncoding
N-methyladenosine
Adenosine