cPLA(2)α targeting to exosomes connects nuclear deformation to LTB(4)-signaling during neutrophil chemotaxis.

Efficient neutrophil chemotaxis requires the integration of mechanical forces and lipid-mediated signaling. While the signaling lipid leukotriene B4 (LTB(4)) reinforces cellular polarity, how mechanical cues regulate its production remains unclear. We now show that cytosolic phospholipase A2α (cPLA(2)α), which is essential for the synthesis of LTB(4), functions as a nuclear curvosensor. cPLA(2)α 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 LTB(4) 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, cPLA(2)α activity drives the chemotactic response to nuclear squeezing by promoting exosomal LTB(4) production and persistence after constriction. These findings uncover a cPLA(2)α-dependent mechanochemical axis linking nuclear architecture to chemotactic efficiency and offer alternative strategies to modulate inflammatory responses.