NCX1 represents an ionic Na+ sensing mechanism in macrophages

Abstract

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.