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

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 N-6-methyladenosine (m(6)A)-dependent manner. Lower levels of MALAT1 promoted the ubiquitination degradation of S100A8/S100A9, thereby impeding p38/mitogen-activated protein kinase phosphorylation and macrophagemediated inflammation. Conclusion: hsa_circ_0004287 inhibits M1 macrophage activation in an m(6)A-dependent manner in AD and psoriasis, and may serve as a general therapeutic candidate for AD and psoriasis.

Automated summary

This study identified a functional unknown circRNA hsa_circ_0004287 that is upregulated in peripheral blood mononuclear cells of both AD and psoriasis patients and mainly expressed by macrophages under inflammatory conditions. Hsa_circ_0004287 reduces the stability of its host gene MALAT1 and inhibits M1 macrophage activation, thereby alleviating skin inflammation in AD and psoriasis.