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

• Published in: Cell 2016-05, Vol.165 (5), p.1160-1170
• Main Authors: Enyedi, Balázs, Jelcic, Mark, Niethammer, Philipp
• Format: Article
• Language: English
• Subjects: Actins - metabolism; Animals; Arachidonate 5-Lipoxygenase - metabolism; Arachidonic Acid - metabolism; Calcium - metabolism; Cell Nucleus - metabolism; Enzyme Activation; Gene Knockdown Techniques; Gene Knockout Techniques; HeLa Cells; Humans; Inflammation - metabolism; Leukocytes - metabolism; Mechanotransduction, Cellular; Nuclear Lamina - metabolism; Phospholipases A2, Cytosolic - metabolism; Zebrafish
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2016.04.016

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 Ca2+ 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. [Display omitted] •Cell swelling and lysis generate proinflammatory eicosanoids through nuclear swelling•Nuclear swelling controls eicosanoid synthesis by activating cPLA2•Swelling-induced nuclear stretch activates cPLA2 by altering enzyme-lipid interactions•F-actin and the nuclear lamina regulate swelling-induced cPLA2 activation Nuclear swelling and membrane stretch acts as a mechanical activation signal for inflammatory lipid signaling that attracts leukocytes to sites of tissue damage.