cPLA₂α targeting to exosomes connects nuclear deformation to LTB₄-signaling during neutrophil chemotaxis.

Abstract

Efficient neutrophil chemotaxis requires the integration of mechanical forces and lipid-mediated signaling. While the signaling lipid leukotriene B4 (LTB₄) reinforces cellular polarity, how mechanical cues regulate its production remains unclear. We now show that cytosolic phospholipase A2α (cPLA₂α), which is essential for the synthesis of LTB₄, functions as a nuclear curvosensor. cPLA₂α responds to nuclear squeezing by localizing to ceramide-rich inner nuclear membrane microdomains and incorporating onto the exofacial surface of nuclear envelope-derived exosomes. This unique topology enables localized LTB₄ synthesis, which synchronizes calcium spikes, promotes myosin light chain II phosphorylation, and sustains polarity and directional persistence after constriction. In neutrophils passing through tight spaces, cPLA₂α activity drives the chemotactic response to nuclear squeezing by promoting exosomal LTB₄ production and persistence after constriction. These findings uncover a cPLA₂α-dependent mechanochemical axis linking nuclear architecture to chemotactic efficiency and offer alternative strategies to modulate inflammatory responses.