Li Yu-Tung, Takaki Eiichi, Ouchi Yuya, Tamai Katsuto
Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan.
StemRIM Inc., Ibaraki, Osaka, 567-0085, Japan.
Cell Mol Life Sci. 2024 Dec 25;82(1):14. doi: 10.1007/s00018-024-05543-2.
Macrophages are versatile myeloid leukocytes with flexible cellular states to perform diverse tissue functions beyond immunity. This plasticity is however often hijacked by diseases to promote pathology. Scanning kinetics of macrophage states by single-cell transcriptomics and flow cytometry, we observed atopic dermatitis drastically exhausted a resident subtype S1. Characterized by FRβ/CD163 expression, S1 exhibited strong efferocytosis and chemoattracted monocytes and eosinophils. Here we have delineated mechanisms regulating monocyte decision to acquire S1 identity in skin. During M-CSF driven macrophage differentiation in healthy skin, FRβ was expressed via intrinsic control of STAT6 and ALK5 activities, and did not require heterotypic cellular crosstalk. In contrast, CD163 expression required exposure to fibroblastic secretion. This process depended on SHP1 activity and involved STAT5 inactivation. Suppressed STAT5 activity caused CD163 expression and rendered macrophage insensitive to further induction by fibroblasts. Parsing coculture experiments with in silico ligand expression, we identified laminin-α2 and type-V collagen secreted by hypodermal fibroblasts as CD163-driving factors. S1 identity loss in AD followed a stepwise cascade: reduced laminins availability first dampened CD163 expression, IL4 and TGFβ subsequently acted on CD163 cells to downregulate FRβ. In AD skin, we showed that imitating this fibroblast-macrophage crosstalk with exogenous laminin-211 encouraged monocyte differentiation to S1 macrophages, fostered homeostatic commitment of extravasated eosinophils, and alleviated dermatitis. Hence, we demonstrated that reinforcing a steady-state cue from hypodermal fibroblasts could override maladaptive pressure on macrophage and restored tissue homeostasis.
巨噬细胞是多功能的髓系白细胞，具有灵活的细胞状态，可执行免疫以外的多种组织功能。然而，这种可塑性常常被疾病利用以促进病理过程。通过单细胞转录组学和流式细胞术对巨噬细胞状态进行扫描动力学分析，我们观察到特应性皮炎使驻留亚型S1严重耗竭。S1以FRβ/CD163表达为特征，表现出强烈的胞葬作用，并对单核细胞和嗜酸性粒细胞具有趋化作用。在此，我们阐述了调节单核细胞在皮肤中获得S1身份的决定机制。在健康皮肤中M-CSF驱动的巨噬细胞分化过程中，FRβ通过STAT6和ALK5活性的内在控制而表达，并不需要异型细胞间的相互作用。相比之下，CD163的表达需要暴露于成纤维细胞分泌产物。这个过程依赖于SHP1活性，并涉及STAT5失活。STAT5活性的抑制导致CD163表达，并使巨噬细胞对成纤维细胞的进一步诱导不敏感。通过计算机模拟配体表达解析共培养实验，我们确定了皮下成纤维细胞分泌的层粘连蛋白-α2和V型胶原是驱动CD163表达的因子。特应性皮炎中S1身份的丧失遵循一个逐步的级联反应：层粘连蛋白可用性降低首先减弱CD163表达，随后IL4和TGFβ作用于CD163细胞以下调FRβ。在特应性皮炎皮肤中，我们表明用外源性层粘连蛋白-211模拟这种成纤维细胞-巨噬细胞的相互作用可促进单核细胞分化为S1巨噬细胞，促进渗出嗜酸性粒细胞的稳态归巢，并减轻皮炎。因此，我们证明增强来自皮下成纤维细胞的稳态信号可以克服对巨噬细胞的适应不良压力并恢复组织稳态。
