The Cell Nucleus Serves as a Mechanotransducer of Tissue Damage-Induced Inflammation

摘要

Tissue damage activates cytosolic phospholipase A(2) (cPLA(2)), releasing arachidonic acid (AA), which is oxidized to proinflammatory eicosanoids by 5-lipoxygenase (5-LOX) on the nuclear envelope. How tissue damage is sensed to activate cPLA(2) is unknown. We investigated this by live imaging in wounded zebrafish larvae, where damage of the fin tissue causes osmotic cell swelling at the wound margin and the generation of a chemotactic eicosanoid signal. Osmotic swelling of cells and their nuclei activates cPla(2) by translocating it from the nucleoplasm to the nuclear envelope. Elevated cytosolic Ca2+ was necessary but not sufficient for cPla(2) translocation, and nuclear swelling was required in parallel. cPla(2) 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 suggest that the nucleus plays a mechanosensory role in inflammation by transducing cell swelling and lysis into proinflammatory eicosanoid signaling.