From tissue damage to nuclear swelling: a novel mechanism of epithelial wound detection

Inflammatory signals have long been known to arise upon cell lysis and necrosis during tissue damage. Recently we have shown that epithelial damage detection is also mediated by direct surveillance of barrier integrity. In zebrafish larvae, osmotic cues from the environment cause cell swelling at the wound margin, which leads to rapid leukocyte recruitment through the activation of cytosolic phospholipase A₂ (cPLA₂). Arachidonic acid released by cPLA₂ is oxidized to pro-inflammatory eicosanoids by 5-lipoxygenase (5-LOX) on the nuclear envelope. Osmotic cell swelling activates cPLA₂ by translocating it from the nucleoplasm to the nuclear envelope. Elevated cytosolic Ca²⁺ is necessary but not sufficient for cPLA₂ translocation, and we now show that nuclear swelling is required as a parallel input. F-actin limits nuclear swelling and cPLA₂ translocation during cell swelling. cPLA₂ translocation upon nuclear swelling was reconstituted in isolated nuclei, and appears to be a simple physical process mediated by tension in the nuclear envelope. Our data show that the cell nucleus serves an unexpected role as the primary mechanosensor for transduction of cell swelling and lysis into pro-inflammatory eicosanoid signaling. Cell swelling and lysis are widely implicated in inflammatory pathology. We propose that the nucleus plays a general mechanosensory role in inflammation, and this explains why cPLA₂ and 5-LOX localize to nuclei in many tissues.