Macrophage subpopulation identity in Drosophila is modulated by apoptotic cell clearance and related signalling pathways.
Macrophage subpopulation identity in Drosophila is modulated by apoptotic cell clearance and related signalling pathways.
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DOI：
10.3389/fimmu.2023.1310117
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发表时间：
2023
影响因子：
7.3
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在果蝇血液中，血细胞谱系的浆细胞代表了脊椎动物巨噬细胞的功能，并已成为研究巨噬细胞功能和行为的既定体内模型。然而，浆细胞作为巨噬细胞模型的使用受到历史观点的限制，即浆细胞代表同质细胞群，与脊椎动物巨噬细胞的高度异质性相反。最近，许多研究小组报道了转录组学方法，表明浆细胞异质性的存在，而我们鉴定了增强子元件，这些增强子元件可识别表现出潜在促炎行为的浆细胞亚群，表明果蝇中浆细胞异质性的保守性。与总浆细胞群相比，这些浆细胞亚群表现出对伤口的增强反应和胞吞率降低。有趣的是，增加对浆细胞的吞噬需求足以减少胚胎中这些浆细胞亚群的大小。然而，这种反应的机制基础尚不清楚。在这里，我们研究了浆细胞亚群如何通过凋亡细胞清除（胞吞作用）需求和相关信号通路进行调节。我们发现，磷脂酰丝氨酸受体 Simu 的缺失可以防止调节特定亚群细胞的吞噬细胞负担增加，而阻断其他凋亡细胞受体则没有显示出这样的拯救。这表明 Simu 依赖性胞吞作用特别参与决定特定亚群的命运。 amo（PKD2 的果蝇同源物）的突变支持了我们最初的发现，amo 是一种钙渗透通道，在 Simu 下游运行，表型 simu 突变体。此外，我们发现 Amo 参与含有凋亡细胞的吞噬体的酸化，表明 pH 值的降低可能与巨噬细胞重编程有关。此外，我们的结果还确定了蜕皮激素受体信号传导（一种与发育过渡期间细胞死亡控制相关的途径）作为浆细胞亚群身份的控制器。总体而言，这些结果确定了浆细胞亚群规范中涉及的基本途径，因此进一步验证了果蝇浆细胞作为这一重要的发育和免疫模型中的巨噬细胞样细胞的异质群体。
In Drosophila blood, plasmatocytes of the haemocyte lineage represent the functional equivalent of vertebrate macrophages and have become an established in vivo model with which to study macrophage function and behaviour. However, the use of plasmatocytes as a macrophage model has been limited by a historical perspective that plasmatocytes represent a homogenous population of cells, in contrast to the high levels of heterogeneity of vertebrate macrophages. Recently, a number of groups have reported transcriptomic approaches which suggest the existence of plasmatocyte heterogeneity, while we identified enhancer elements that identify subpopulations of plasmatocytes which exhibit potentially pro-inflammatory behaviours, suggesting conservation of plasmatocyte heterogeneity in Drosophila. These plasmatocyte subpopulations exhibit enhanced responses to wounds and decreased rates of efferocytosis when compared to the overall plasmatocyte population. Interestingly, increasing the phagocytic requirement placed upon plasmatocytes is sufficient to decrease the size of these plasmatocyte subpopulations in the embryo. However, the mechanistic basis for this response was unclear. Here, we examine how plasmatocyte subpopulations are modulated by apoptotic cell clearance (efferocytosis) demands and associated signalling pathways. We show that loss of the phosphatidylserine receptor Simu prevents an increased phagocytic burden from modulating specific subpopulation cells, while blocking other apoptotic cell receptors revealed no such rescue. This suggests that Simu-dependent efferocytosis is specifically involved in determining fate of particular subpopulations. Supportive of our original finding, mutations in amo (the Drosophila homolog of PKD2), a calcium-permeable channel which operates downstream of Simu, phenocopy simu mutants. Furthermore, we show that Amo is involved in the acidification of the apoptotic cell-containing phagosomes, suggesting that this reduction in pH may be associated with macrophage reprogramming. Additionally, our results also identify Ecdysone receptor signalling, a pathway related to control of cell death during developmental transitions, as a controller of plasmatocyte subpopulation identity. Overall, these results identify fundamental pathways involved in the specification of plasmatocyte subpopulations and so further validate Drosophila plasmatocytes as a heterogeneous population of macrophage-like cells within this important developmental and immune model.