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 (cPLA₂α), which is essential for the synthesis of LTB ₄ , functions as a nuclear curvosensor. cPLA₂α responds to nuclear constrictions 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 promotes myosin light chain II phosphorylation, and sustains polarity and directional persistence after constriction. In neutrophils squeezing through small constrictions, loss of cPLA₂α impairs nuclear curvature sensing, exosomal LTB ₄ production, and post-constriction motility. These findings uncover a cPLA ₂ -dependent mechano-chemical axis linking nuclear architecture to chemotactic efficiency and offering new strategies to modulate inflammatory responses.