M1 polarization of macrophages promotes stress-induced hair loss via interleukin-18 and interleukin-1β
M1 polarization of macrophages promotes stress-induced hair loss via interleukin-18 and interleukin-1β
复制标题
DOI：
10.1002/jcp.31181
复制
发表时间：
2024-01-14
影响因子：
5.6
通讯作者：
Huang，Bihui
中科院分区：
文献类型：
--
作者：
Xiao，Xing;Gao，Ying;Huang，Bihui
压力导致的脱发是一个普遍的健康问题，其机制尚不清楚，有效的治疗方案尚未推出。在这项研究中，我们调查了压力导致的脱发是否与免疫微环境失衡有关。在应激小鼠模型中筛选皮肤渗透的免疫细胞，我们发现在应激诱导下巨噬细胞显著增加。巨噬细胞的清除将小鼠从应激诱导的脱发和皮肤中毛囊干细胞(HfSCs)的枯竭中拯救出来，证明了巨噬细胞在触发应激反应中的脱发中的作用。进一步的流式细胞术分析显示，在应激条件下，小鼠的M1表型巨噬细胞显著增加。在寻找介导应激诱导的巨噬细胞极化的体液因素时，我们发现应激小鼠血液中的去甲肾上腺素(NE)激素水平升高。此外，体内和体外研究证实，NE可以通过β-肾上腺素能受体ADRB2诱导巨噬细胞向M1极化。转录组、酶联免疫吸附试验和免疫印迹分析显示，NE处理的巨噬细胞NLRP3/Caspase-1炎症信号通路及其下游效应因子IL-18和IL-1β(IL-1β)显著上调。然而，用ICI118551抑制NE受体ADRB2后，NLRP3/Caspase-1、IL-18和IL-1β的表达上调。事实上，IL-18和IL-1β治疗会导致hfSCs的凋亡。更重要的是，阻断IL-18和IL-1β信号逆转了皮肤器官模型中hfSCs的枯竭，并减轻了应激诱导的小鼠脱发。综上所述，本研究证实了神经(应激)-内分泌(NE)-免疫(M1巨噬细胞)轴在应激诱导脱发中的作用，并提示IL-18或IL-1β可能是有前途的治疗靶点。
Stress‐induced hair loss is a prevalent health concern, with mechanisms that remain unclear, and effective treatment options are not yet available. In this study, we investigated whether stress‐induced hair loss was related to an imbalanced immune microenvironment. Screening the skin‐infiltrated immune cells in a stressed mouse model, we discovered a significant increase in macrophages upon stress induction. Clearance of macrophages rescues mice from stress‐induced 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‐induced macrophage polarization, we found that the hormone Norepinephrine (NE) was elevated in the blood of stressed mice. In addition, in‐vivo and in‐vitro studies confirm that NE can induce macrophage polarization toward M1 through the β‐adrenergic receptor, Adrb2. Transcriptome, enzyme‐linked immunosorbent assay (ELISA), and western blot analyses reveal that the NLRP3/caspase‐1 inflammasome signaling and its downstream effector interleukin 18 (IL‐18) and interleukin 1 beta (IL‐1β) were significantly upregulated in the NE‐treated macrophages. However, inhibition of the NE receptor Adrb2 with ICI118551 reversed the upregulation of NLRP3/caspase‐1, IL‐18, and IL‐1β. Indeed, IL‐18 and IL‐1β treatments lead to apoptosis of HFSCs. More importantly, blocking IL‐18 and IL‐1β signals reversed HFSCs depletion in skin organoid models and attenuated stress‐induced hair shedding in mice. Taken together, this study demonstrates the role of the neural (stress)‐endocrine (NE)‐immune (M1 macrophages) axis in stress‐induced hair shedding and suggestes that IL‐18 or IL‐1β may be promising therapeutic targets.