N6-methyladenosine modification-tuned lipid metabolism controls skin immune homeostasis via regulating neutrophil chemotaxis

被引：1

作者：

Cui, Lian ^{[1
,2
]}

Wu, You ^{[3
,4
]}

Chen, Zeyu ^{[1
,2
]}

Li, Bingjie ^{[1
,2
,5
]}

Cai, Jiangluyi ^{[1
,2
]}

Chang, Zhanhe ^{[3
,4
]}

Xiao, Weide ^{[6
,7
]}

Wang, Yuanyuan ^{[1
,2
]}

Yang, Nan ^{[1
,2
]}

Wang, Yu ^{[1
,2
]}

Yu, Zengyang ^{[2
,8
]}

Yao, Lingling ^{[1
,2
]}

Ma, Rui ^{[1
,2
]}

Wang, Xin ^{[1
,2
]}

Chen, Youdong ^{[1
,2
,8
]}

Chen, Qianyu ^{[1
,2
]}

Mei, Hao ^{[2
,8
]}

Lan, Zhiyi ^{[2
,8
]}

Yu, Yingyuan ^{[1
,2
]}

Chen, Rongfen ^{[1
,2
]}

Wu, Xingbiao ^{[1
]}

Yu, Qian ^{[2
,8
]}

Lu, Jiajing ^{[1
,2
]}

Yu, Ning ^{[1
,2
]}

Zhang, Xilin ^{[1
,2
]}

Liu, Jun ^{[6
,7
]}

Zhang, Lingjuan ^{[9
]}

Lai, Yuping ^{[10
]}

Gao, Shaorong ^{[4
,11
]}

Gao, Yawei ^{[3
,4
]}

Guo, Chunyuan ^{[1
,2
]}

Shi, Yuling ^{[1
,2
]}

机构：

[1] Tongji Univ, Shanghai Skin Dis Hosp, Sch Med, Dept Dermatol, Shanghai, Peoples R China

[2] Tongji Univ, Inst Psoriasis, Sch Med, Shanghai, Peoples R China

[3] Tongji Univ, Shanghai East Hosp, Sch Life Sci & Technol, Inst Regenerat Med,Shanghai Key Lab Signaling & Di, Shanghai, Peoples R China

[4] Tongji Univ, Frontier Sci Ctr Stem Cell Res, Shanghai, Peoples R China

[5] Univ Chinese Acad Sci, Chinese Acad Sci, Shanghai Inst Nutr & Hlth, CAS Key Lab Computat Biol, Shanghai, Peoples R China

[6] Peking Univ, Sch Life Sci, State Key Lab Prot & Plant Gene Res, Beijing 100871, Peoples R China

[7] Peking Univ, Peking Tsinghua Ctr Life Sci, Beijing 100871, Peoples R China

[8] Tongji Univ, Shanghai Peoples Hosp 10, Sch Med, Dept Dermatol, Shanghai, Peoples R China

[9] Xiamen Univ, Sch Pharmaceut Sci, State Key Lab Cellular Stress Biol, Xiamen 361102, Peoples R China

[10] East China Normal Univ, Sch Life Sci, Shanghai Frontiers Sci Ctr Genome Editing & Cell T, Shanghai Key Lab Regulatory Biol, Shanghai, Peoples R China

[11] Tongji Univ, Infant Hosp, Clin & Translat Res Ctr Shanghai Matern 1, Shanghai Key Lab Signaling & Dis Res, Shanghai, Peoples R China

来源：

SCIENCE ADVANCES | 2024年 / 10卷 / 40期

基金：

国家重点研发计划; 中国国家自然科学基金;

关键词：

ATOPIC-DERMATITIS; FATTY-ACIDS; PSORIASIS; METHYLATION; CELLS;

D O I：

10.1126/sciadv.adp5332

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Disrupted N-6-methyladenosine (m(6)A) modification modulates various inflammatory disorders. However, the role of m(6)A in regulating cutaneous inflammation remains elusive. Here, we reveal that the m(6)A and its methyltransferase METTL3 are down-regulated in keratinocytes in inflammatory skin diseases. Inducible deletion of Mettl3 in murine keratinocytes results in spontaneous skin inflammation and increases susceptibility to cutaneous inflammation with activation of neutrophil recruitment. Therapeutically, restoration of m(6)A alleviates the disease phenotypes in mice and suppresses inflammation in human biopsy specimens. We support a model in which m(6)A modification stabilizes the mRNA of the lipid-metabolizing enzyme ELOVL6 via the m(6)A reader IGF2BP3, leading to a rewiring of fatty acid metabolism with a reduction in palmitic acid accumulation and, consequently, suppressing neutrophil chemotaxis in cutaneous inflammation. Our findings highlight a previously unrecognized epithelial-intrinsic m(6)A modification-lipid metabolism pathway that is essential for maintaining epidermal and immune homeostasis and lay the basis for potential therapeutic targeting of m(6)A modulators to attenuate inflammatory skin diseases.

引用

页数：19

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