Inflammation and infection can trigger local tissue Na⁺ accumulation. This Na⁺-rich environment boosts proinflammatory activation of monocyte/macrophage-like cells (MΦs) and their antimicrobial activity. Enhanced Na⁺-driven MΦ function requires the osmoprotective transcription factor nuclear factor of activated T cells 5 (NFAT5), which augments nitric oxide (NO) production and contributes to increased autophagy. However, the mechanism of Na⁺ sensing in MΦs remained unclear. High extracellular Na⁺ levels (high salt [HS]) trigger a substantial Na⁺ influx and Ca²⁺ loss. Here, we show that the Na⁺/Ca²⁺ exchanger 1 (NCX1, also known as solute carrier family 8 member A1 [SLC8A1]) plays a critical role in HS-triggered Na⁺ influx, concomitant Ca²⁺ efflux, and subsequent augmented NFAT5 accumulation. Moreover, interfering with NCX1 activity impairs HS-boosted inflammatory signaling, infection-triggered autolysosome formation, and subsequent antibacterial activity. Taken together, this demonstrates that NCX1 is able to sense Na⁺ and is required for amplifying inflammatory and antimicrobial MΦ responses upon HS exposure. Manipulating NCX1 offers a new strategy to regulate MΦ function.

炎症和感染可引发局部组织Na ⁺蓄积。这种富含 Na ⁺的环境可促进单核细胞/巨噬细胞样细胞 (MΦ) 的促炎激活及其抗菌活性。增强的 Na ⁺驱动的 MΦ 功能需要激活 T 细胞的渗透保护转录因子核因子 5 (NFAT5)，它会增加一氧化氮 (NO) 的产生并有助于增加自噬。然而，MΦs 中 Na ⁺传感的机制仍不清楚。高细胞外 Na ⁺水平（高盐 [HS]）会引发大量 Na ⁺流入和 Ca ²⁺损失。在这里，我们表明 Na ⁺ /Ca ²⁺交换器 1（NCX1，也称为溶质载体家族 8 成员 A1 [SLC8A1]）在 HS 触发的 Na ⁺流入、伴随的 Ca ²⁺流出以及随后的过程中发挥着关键作用。增强 NFAT5 积累。此外，干扰 NCX1 活性会损害 HS 增强的炎症信号、感染触发的自溶酶体形成以及随后的抗菌活性。总而言之，这表明 NCX1 能够感知 Na ⁺ ，并且是在 H2S 暴露后放大炎症和抗菌 MΦ 反应所必需的。操纵 NCX1 提供了调节 MΦ 功能的新策略。