Editors' ChoiceCell Biology

Swelling to attract leukocytes

Sci. Signal.  31 May 2016:
Vol. 9, Issue 430, pp. ec129
DOI: 10.1126/scisignal.aag2278

Wounding of epithelial barriers increases the hypotonicity of the underlying tissues, triggering cell swelling, which is associated with the translocation of a form of phospholipase A2, cPLA2, from the nucleoplasm to the inner nuclear membrane in a Ca2+-dependent manner. cPLA2 generates arachidonic acid in the membrane, which is metabolized into eicosanoids which are released from cells and recruit leukocytes to the wound site. Enyedi et al. (see also Chang and Gundersen) found that the swelling of nuclei, which occurs in hypotonic or dead cells, induces the translocation of cPLA2 to the inner nuclear membrane. In zebrafish expressing a nuclear-targeted Ca2+ reporter, tail wounding triggered different Ca2+ transients, including an oscillatory activity that was sustained and extended beyond the wound margin. In zebrafish also expressing a fluorescently tagged cPLA2 construct, cells in which cPLA2 had translocated to the inner nuclear membrane did not completely overlap with cells with the oscillatory Ca2+ activity, suggesting that Ca2+ signals were not sufficient for cPLA2 translocation after tail wounding. Both the oscillatory activity and the translocation of cPla2 were blocked when the wounded tails were immersed in isotonic bathing solutions. In HeLa cells, hypotonic shock induced the translocation of fluorescently tagged cPLA2 to the inner nuclear membrane and arachidonic acid release, and cPLA2 translocation did not occur below a threshold Ca2+ concentration. In both HeLa cells and epithelial cells of zebrafish, actin depolymerization enhanced the increase in nuclear volume and cPLA2 translocation induced by hypotonic shock, suggesting a role for the actin cytoskeleton in regulating nuclear swelling. Nuclear swelling under controlled osmotic conditions in the presence of increased Ca2+ triggered cPLA2 translocation to the inner nuclear membrane in HeLa cells, indicating that hypotonicity was not required. Cell swelling also occurs in necrotic tissues. When amputated zebrafish tails were bathed in isotonic conditions that would not induce cell swelling, the presence of dead HeLa cells in the solution triggered the recruitment of leukocytes to injured tails. The ability of the dead HeLa cells to stimulate leukocyte recruitment required the cells to have swollen nuclei and for cPLA2 to be present. These results indicate that necrotic cells can recruit leukocytes in a manner similar to cells in damaged tissues and suggest that this pathway could operate in different types of inflammatory events.

B. Enyedi, M. Jelcic, P. Niethammer, The cell nucleus serves as a mechanotransducer of tissue damage-induced inflammation. Cell 165, 1160–1170 (2016). [PubMed]

W. Chang, G. G. Gundersen, Swollen nuclei signal from the grave. Cell 165, 1051–1052 (2016). [PubMed]

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