Infiltration of monocyte-derived cells to sites of infection and injury is greater in males than in females, due in part, to increased chemotaxis, the process of directed cell movement toward a chemical signal. The mechanisms governing sexual dimorphism in chemotaxis are not known. We hypothesized a role for the store-operated calcium entry (SOCE) pathway in regulating chemotaxis by modulating leading and trailing edge membrane dynamics. We measured the chemotactic response of bone marrow-derived macrophages migrating toward complement component 5a (C5a). Chemotactic ability was dependent on sex and inflammatory phenotype (M0, M1, and M2), and correlated with SOCE. Notably, females exhibited a significantly lower magnitude of SOCE than males. When we knocked out the SOCE gene, stromal interaction molecule 1 (STIM1), it eliminated SOCE and equalized chemotaxis across both sexes. Analysis of membrane dynamics at the leading and trailing edges showed that STIM1 influences chemotaxis by facilitating retraction of the trailing edge. Using BTP2 to pharmacologically inhibit SOCE mirrored the effects of STIM1 knockout, demonstrating a central role of STIM/Orai-mediated calcium signaling. Importantly, by monitoring the recruitment of adoptively transferred monocytes in an model of peritonitis, we show that increased infiltration of male monocytes during infection is dependent on STIM1. These data support a model in which STIM1-dependent SOCE is necessary and sufficient for mediating the sex difference in monocyte recruitment and macrophage chemotactic ability by regulating trailing edge dynamics.

中文翻译：

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STIM1依赖的钙库操纵的钙进入介导巨噬细胞趋化和单核细胞募集的性别差异


男性中单核细胞衍生的细胞对感染和损伤部位的浸润比女性更多，部分原因是趋化性增加，即定向细胞向化学信号移动的过程。趋化性中控制性二态性的机制尚不清楚。我们假设钙池操纵的钙进入（SOCE）途径通过调节前缘和后缘膜动力学来调节趋化性。我们测量了骨髓源性巨噬细胞向补体成分 5a (C5a) 迁移的趋化反应。趋化能力取决于性别和炎症表型（M0、M1 和 M2），并与 SOCE 相关。值得注意的是，女性的 SOCE 幅度明显低于男性。当我们敲除 SOCE 基因、基质相互作用分子 1 (STIM1) 时，它消除了 SOCE 并平衡了两性的趋化性。对前缘和后缘的膜动力学分析表明，STIM1 通过促进后缘的收缩来影响趋化性。使用 BTP2 从药理上抑制 SOCE 反映了 STIM1 敲除的效果，证明了 STIM/Orai 介导的钙信号传导的核心作用。重要的是，通过监测腹膜炎模型中过继转移的单核细胞的招募，我们发现感染期间雄性单核细胞浸润的增加依赖于 STIM1。这些数据支持一个模型，其中 STIM1 依赖性 SOCE 对于通过调节后缘动力学来介导单核细胞募集和巨噬细胞趋化能力的性别差异是必要且充分的。