Editors' ChoiceInflammation

Coordinating a neutrophil swarm

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Science Signaling  04 Aug 2020:
Vol. 13, Issue 643, eabe0797
DOI: 10.1126/scisignal.abe0797

Ca2+ and ATP signaling control the self-organized, collective behaviors of neutrophils at wound sites.

Neutrophils are recruited to sites of tissue damage by various damage-associated molecular patterns (DAMPs) and other chemoattractants, and they exhibit coordinated behaviors at the wound site. This switch from autonomous chemotaxis to collective behaviors (swarming) depends on leukotriene B4 (LTB4) and is reminiscent of behaviors triggered by quorum sensing in bacteria (see Palomino-Segura and Hidalgo). To follow neutrophil swarming in vivo, Poplimont et al. generated zebrafish expressing a fluorescent Ca2+ sensor and a fluorescently tagged form of 5-LO, an enzyme that is required for LTB4 biosynthesis and translocates to the nuclear envelope when active, specifically in neutrophils. Neutrophils migrating toward sterile wounds showed occasional Ca2+ flashes, but the signals increased in both intensity and duration after the cells congregated at the wound site. LTB4 biosynthesis correlated with the most intense Ca2+ flashes, and both responses occurred when neutrophils made contact with damaged tissue or other neutrophils already at the wound site. The Ca2+ alarm signals, LTB4 biosynthesis, and neutrophil clustering depended on Ca2+ influx through plasma membrane channels gated by ATP and on the release of ATP from neutrophils through connexin 43 (Cx43) hemichannels, suggesting that ATP acted as both a wound-derived DAMP to initiate swarming and a neutrophil-derived signal that amplified collective behaviors. At wounds in the presence of fluorescently labeled Pseudomonas aeruginosa, neutrophils exhibited the same chemotactic and collective behaviors observed in sterile wounds and rapidly cleared the bacteria from the wound; however, expression of a dominant-negative form of Cx43 reduced Ca2+ signaling, clustering, and bacterial clearance. How these collective behaviors that protect against infection are attenuated during wound resolution to avoid tissue damage remains an open question (see Palomino-Segura and Hidalgo).

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