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In this study, we investigated whether stress\u2010induced hair loss was related to an imbalanced immune microenvironment. Screening the skin\u2010infiltrated immune cells in a stressed mouse model, we discovered a significant increase in macrophages upon stress induction. Clearance of macrophages rescues mice from stress\u2010induced hair shedding and depletion of hair follicle stem cells (HFSCs) in the skin, demonstrating the role of macrophages in triggering hair loss in response to stress. Further flow cytometry analysis revealed a significant increase in M1 phenotype macrophages in mice under stressed conditions. In searching for humoral factors mediating stress\u2010induced macrophage polarization, we found that the hormone Norepinephrine (NE) was elevated in the blood of stressed mice. In addition, in\u2010vivo and in\u2010vitro studies confirm that NE can induce macrophage polarization toward M1 through the \u03b2\u2010adrenergic receptor, Adrb2. Transcriptome, enzyme\u2010linked immunosorbent assay (ELISA), and western blot analyses reveal that the NLRP3\/caspase\u20101 inflammasome signaling and its downstream effector interleukin 18 (IL\u201018) and interleukin 1 beta (IL\u20101\u03b2) were significantly upregulated in the NE\u2010treated macrophages. However, inhibition of the NE receptor Adrb2 with ICI118551 reversed the upregulation of NLRP3\/caspase\u20101, IL\u201018, and IL\u20101\u03b2. Indeed, IL\u201018 and IL\u20101\u03b2 treatments lead to apoptosis of HFSCs. More importantly, blocking IL\u201018 and IL\u20101\u03b2 signals reversed HFSCs depletion in skin organoid models and attenuated stress\u2010induced hair shedding in mice. Taken together, this study demonstrates the role of the neural (stress)\u2010endocrine (NE)\u2010immune (M1 macrophages) axis in stress\u2010induced hair shedding and suggestes that IL\u201018 or IL\u20101\u03b2 may be promising therapeutic targets.<\/jats:p>","DOI":"10.1002\/jcp.31181","type":"journal-article","created":{"date-parts":[[2024,1,14]],"date-time":"2024-01-14T06:33:18Z","timestamp":1705213998000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["M1 polarization of macrophages promotes stress\u2010induced hair loss via interleukin\u201018 and interleukin\u20101\u03b2"],"prefix":"10.1002","volume":"239","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5771-0677","authenticated-orcid":false,"given":"Xing","family":"Xiao","sequence":"first","affiliation":[{"name":"Scientific Research Center The Seventh Affiliated Hospital of Sun Yat\u2010sen University Shenzhen China"},{"name":"Digestive Disease Center 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