CSF1R 抑制作用会影响多种免疫细胞群，并在瘦小鼠中诱导组织特异性代谢效应。

AIMS/HYPOTHESIS: Colony stimulating factor 1 (CSF1) promotes the proliferation, differentiation and survival of macrophages, which have been implicated in both beneficial and detrimental effects on glucose metabolism. However, the physiological role of CSF1 signalling in glucose homeostasis and the potential therapeutic implications of modulating this pathway are not known. We aimed to study the composition of tissue macrophages (and other immune cells) following CSF1 receptor (CSF1R) inhibition and elucidate the metabolic consequences of CSF1R inhibition. METHODS: We assessed immune cell populations in various organs by flow cytometry, and tissue-specific metabolic effects by hyperinsulinaemic-euglycaemic clamps and insulin secretion assays in mice fed a chow diet containing PLX5622 (a CSF1R inhibitor) or a control diet. RESULTS: CSF1R inhibition depleted macrophages in multiple tissues while simultaneously increasing eosinophils and group 2 innate lymphoid cells. These immunological changes were consistent across different organs and were sex independent and reversible after cessation of the PLX5622. CSF1R inhibition improved hepatic insulin sensitivity but concomitantly impaired insulin secretion. In healthy islets, we found a high frequency of IL-1β islet macrophages. Their depletion by CSF1R inhibition led to downregulation of macrophage-related pathways and mediators of cytokine activity, including Nlrp3, suggesting IL-1β as a candidate insulin secretagogue. Partial restoration of physiological insulin secretion was achieved by injecting recombinant IL-1β prior to glucose stimulation in mice lacking macrophages. CONCLUSIONS/INTERPRETATION: Macrophages and macrophage-derived factors, such as IL-1β, play an important role in physiological insulin secretion. A better understanding of the tissue-specific effects of CSF1R inhibition on immune cells and glucose homeostasis is crucial for the development of targeted immune-modulatory treatments in metabolic disease. DATA AVAILABILITY: The RNA-Seq dataset is available in the Gene Expression Omnibus (GEO) under the accession number GSE189434 ( http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE189434 ).

目的/假设：集落刺激因子 1（CSF1）促进巨噬细胞的增殖、分化和存活，而巨噬细胞对葡萄糖代谢既有有益影响，也有有害影响。然而，CSF1 信号在葡萄糖稳态中的生理作用以及调节该途径的潜在治疗意义尚不清楚。我们旨在研究 CSF1 受体（CSF1R）抑制后组织巨噬细胞（和其他免疫细胞）的组成，并阐明 CSF1R 抑制的代谢后果。

方法：我们通过流式细胞术评估了各种器官中的免疫细胞群体，并通过高胰岛素-正葡萄糖钳夹和胰岛素分泌测定法评估了喂食含有 PLX5622（CSF1R 抑制剂）或对照饮食的小鼠的组织特异性代谢效应。

结果：CSF1R 抑制耗尽了多种组织中的巨噬细胞，同时增加了嗜酸性粒细胞和 2 型固有淋巴细胞。这些免疫学变化在不同器官中是一致的，并且在 PLX5622 停止后是性别独立和可逆的。CSF1R 抑制改善了肝脏胰岛素敏感性，但同时损害了胰岛素分泌。在健康的胰岛中，我们发现了大量的 IL-1β 胰岛巨噬细胞。CSF1R 抑制导致这些巨噬细胞耗竭，进而下调了与巨噬细胞相关的途径和细胞因子活性的介质，包括 Nlrp3，提示 IL-1β 是胰岛素分泌的候选物。在缺乏巨噬细胞的小鼠中，在葡萄糖刺激前注射重组 IL-1β 可部分恢复生理胰岛素分泌。

结论/解释：巨噬细胞和巨噬细胞衍生的因子，如 IL-1β，在生理胰岛素分泌中发挥重要作用。更好地了解 CSF1R 抑制对免疫细胞和葡萄糖稳态的组织特异性影响，对于开发代谢性疾病的靶向免疫调节治疗至关重要。

数据可用性：RNA-Seq 数据集可在基因表达综合数据库（GEO）中获得， accession number GSE189434（http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE189434）。