title: The Cell Nucleus Serves as a Mechanotransducer of Tissue Damage-Induced Inflammation.
abstract: Tissue damage activates cytosolic phospholipase A2 (cPLA2), 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 cPLA2 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 cPla2 by translocating it from the nucleoplasm to the nuclear envelope. Elevated cytosolic Ca(2+) was necessary but not sufficient for cPla2 translocation, and nuclear swelling was required in parallel. 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 suggest that the nucleus plays a mechanosensory role in inflammation by transducing cell swelling and lysis into proinflammatory eicosanoid signaling.
authors.affiliation: Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Balázs
authors.initials: B
authors.lastname: Enyedi
authors.affiliation: Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Jelcic
authors.affiliation: Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: niethamp@mskcc.org.
authors.forename: Philipp
authors.initials: P
authors.lastname: Niethammer
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D016718:Arachidonic Acid / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism*; D004789:Enzyme Activation; D055785:Gene Knockdown Techniques; D055786:Gene Knockout Techniques; D006367:HeLa Cells; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D007962:Leukocytes / Q000378:metabolism; D040542:Mechanotransduction, Cellular; D034881:Nuclear Lamina / Q000378:metabolism; D054510:Phospholipases A2, Cytosolic / Q000378:metabolism; D015027:Zebrafish
chemical_list: D000199:Actins; D016718:Arachidonic Acid; D001094:Arachidonate 5-Lipoxygenase; D054510:Phospholipases A2, Cytosolic; D002118:Calcium