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 Ca 2+ loss. Here, we show that the Na + /Ca 2+ exchanger 1 (NCX1, also known as solute carrier family 8 member A1 [SLC8A1]) plays a critical role in HS-triggered Na + influx, concomitant Ca 2+ 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.

Macrophages as host, effector and immunoregulatory cells in leishmaniasis: Impact of tissue micro-environment and metabolism

“…Jantsch et al provided direct and firm evidence that increased concentrations of Na + in the tissue following a high-salt diet improved control of L. major in vivo via NFAT5-dependent induction of NOS2 [154] . The Na + /Ca 2+ exchanger 1 (NCX1, also known as solute carrier family 8 member A1 [SLC8A1]) accounted for the Na + influx during exposure of macrophages to high salt conditions [155] . Recent data indicate that the effect of tissue osmolarity on phagocyte functions might not be restricted to classically activated (M1) macrophages, but could also pertain to alternatively activated (M2) macrophages [156] .…”

The mechanism of ions in pulmonary hypertension

“…NCX is also engaged in insulin secretion, calcium reabsorption in the kidney, and learning and memory related to the hippocampus. 151,154 We will not elaborate on it here.…”

Sodium and its manifold impact on our immune system

“…In contrast to epithelial cells, immune cells lack an apical-basal axis orientation, indicating that their ability to handle changes in the local ionic composition will differ from the mechanisms in epithelial cells. In addition, in macrophages for instance, the resting membrane potential is not as negative as in epithelial cells [58,59], which has implications on the activity and thermodynamics of channels, exchangers, and transporters. Our group reported that the Na + /Ca 2+ exchanger plays an important role in the detection of increases in local extracellular sodium levels and contributes to amplifying proinflammatory mouse macrophage responses [58].…”

“…In addition, in macrophages for instance, the resting membrane potential is not as negative as in epithelial cells [58,59], which has implications on the activity and thermodynamics of channels, exchangers, and transporters. Our group reported that the Na + /Ca 2+ exchanger plays an important role in the detection of increases in local extracellular sodium levels and contributes to amplifying proinflammatory mouse macrophage responses [58]. However, sodium handling ensuing cellular responses remain undetermined and we do not know how other immune cells might detect and/or handle excess sodium amounts.…”

“…The effect of sodium on the antimicrobial properties of murine macrophages. Na + /Ca 2+ exchanger 1 (NCX1) plays an important role in the detection of extracellular Na + concentrations by macrophages [58]. NCX1-facilitated Na + entry triggers a Ca 2+ loss and enhances NFAT5 accumulation [58].…”