<i>N</i> <sup>6</sup> -methyladenosine modification–tuned lipid metabolism controls skin immune homeostasis via regulating neutrophil chemotaxis
Disrupted <i>N</i><sup>6</sup>-methyladenosine (m<sup>6</sup>A) modification modulates various inflammatory disorders. However, the role of m<sup>6</sup>A in regulating cutaneous inflammation remains elusive. Here, we reveal that the m<sup>6</sup>A and its methyltransferase METTL3 are down-regulated in keratinocytes in inflammatory skin diseases. Inducible deletion of <i>Mettl3</i> in murine keratinocytes results in spontaneous skin inflammation and increases susceptibility to cutaneous inflammation with activation of neutrophil recruitment. Therapeutically, restoration of m<sup>6</sup>A alleviates the disease phenotypes in mice and suppresses inflammation in human biopsy specimens. We support a model in which m<sup>6</sup>A modification stabilizes the mRNA of the lipid-metabolizing enzyme ELOVL6 via the m<sup>6</sup>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<sup>6</sup>A modification-lipid metabolism pathway that is essential for maintaining epidermal and immune homeostasis and lay the basis for potential therapeutic targeting of m<sup>6</sup>A modulators to attenuate inflammatory skin diseases.
Authors
- Chunyuan Guo (ORCID: https://orcid.org/0000-0001-6769-1713)
- Weide Xiao (ORCID: https://orcid.org/0000-0002-1456-4240)
- Ling‐juan Zhang (ORCID: https://orcid.org/0000-0001-6937-4578)
- Qian Yu (ORCID: https://orcid.org/0000-0002-2144-5637)
- Hao Mei (ORCID: https://orcid.org/0000-0002-0125-7153)
- You Wu
- Jiangluyi Cai
- Yuling Shi (ORCID: https://orcid.org/0000-0002-1273-7881)
- Lingling Yao (ORCID: https://orcid.org/0000-0002-1641-1256)
- Jiajing Lu (ORCID: https://orcid.org/0000-0002-0827-0596)
- Yawei Gao (ORCID: https://orcid.org/0000-0001-8946-9697)
- Shaorong Gao (ORCID: https://orcid.org/0000-0003-1041-3928)
- Youdong Chen (ORCID: https://orcid.org/0000-0002-1388-9297)
- Nan Yang (ORCID: https://orcid.org/0000-0002-6509-6328)
- Yingyuan Yu (ORCID: https://orcid.org/0000-0001-6369-3738)
- Zhiyi Lan (ORCID: https://orcid.org/0000-0001-5519-2474)
- Yuping Lai (ORCID: https://orcid.org/0000-0001-7445-6738)
- Xin Wang (ORCID: https://orcid.org/0000-0001-8051-1481)
- Jun Liu (ORCID: https://orcid.org/0000-0002-2498-9963)
- Yuanyuan Wang (ORCID: https://orcid.org/0000-0003-4881-6044)
- Yu Wang (ORCID: https://orcid.org/0000-0002-6005-3062)
- Bingjie Li (ORCID: https://orcid.org/0000-0002-4871-7444)
- Xilin Zhang (ORCID: https://orcid.org/0000-0002-5204-4086)
- Zengyang Yu (ORCID: https://orcid.org/0000-0001-9849-0340)
- Zeyu Chen (ORCID: https://orcid.org/0000-0001-6393-1986)
- Ning Yu (ORCID: https://orcid.org/0000-0001-7140-5505)
- Xingbiao Wu
- Qianyu Chen (ORCID: https://orcid.org/0000-0002-4098-5735)
- Lian Cui (ORCID: https://orcid.org/0000-0003-0997-6424)
- Rongfen Chen (ORCID: https://orcid.org/0000-0002-6589-3052)
- Rui Ma (ORCID: https://orcid.org/0009-0004-1482-8762)
- Zhanhe Chang
Institutions
- Tongji University (CN)
- Xiamen University (CN)
- Peking University (CN)
- Shanghai Institute of Nutrition and Health (CN)
- Shanghai East Hospital (CN)
- Shanghai Tenth People's Hospital (CN)
- Shanghai First Maternity and Infant Hospital (CN)
- Shanghai Skin Disease Hospital (CN)
- Center for Life Sciences (CN)
- University of Chinese Academy of Sciences (CN)
- East China Normal University (CN)
Publication Details
- Journal
- Science Advances
- Published
- 2024-10-02
- DOI
- https://doi.org/10.1126/sciadv.adp5332
- Citations
- 14
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 3.27