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Abstract
SummaryNeutrophils are major inflammatory cells that rapidly infiltrate wounds to provide antimicrobial functions. Within the damaged tissue, neutrophil migration behavior often switches from exploratory patrolling to coordinated swarming, giving rise to dense clusters that further disrupt tissue architecture. This aggregation response is self-organized by neutrophil paracrine chemoattractant signaling (most notably of the inflammatory mediator leukotriene B4 [LTB4]). The coordination mechanism and possible evolutionary benefits of neutrophil swarms are elusive. Here, we show that neutrophil swarms require mutual reinforcement of damage signaling at the wound core. New biosensors and live imaging in zebrafish revealed that neutrophil chemoattractant synthesis is triggered by a sustained calcium flux upon contact with necrotic tissue that requires sensing of the damage signal ATP. This “calcium alarm” signal rapidly propagates in the nascent neutrophil cluster in a contact-dependent manner via connexin-43 (Cx43) hemichannels, which are mediators of active ATP release. This enhances chemoattractant biosynthesis in the growing cluster, which is instrumental for coordinated motion and swarming. Inhibition of neutrophil Cx43 compromises clearance of wound-colonizing P. aeruginosa bacteria and exacerbates infection-induced morbidity. Thus, cooperative production of alarm signals among pioneer clustering neutrophils fuels the growth of dense antimicrobial cell masses that effectively seal off breached tissue barriers from opportunistic pathogens.
Highlights
Tissue damage triggers rapid recruitment of immune cells, with neutrophils as prime infiltrators [1, 2]
To establish the role of neutrophil LTB4 production in this model, we generated a transgenic zebrafish line, Tg(lyz:lta4h-EGFP), expressing leukotriene A4 hydrolase (LTA4H), an enzyme that catalyzes the conversion of LTA4 into LTB4 [17], the final step in LTB4 biosynthesis
Because swarms are more likely to occur under high neutrophil density [8, 15, 19], we visualized the behavior of neutrophils after acute laser wound injury at a site rich in neutrophils, the caudal hematopoietic tissue (CHT), using two-photon ablation (Figures 1A and S1E; Video S1)
Summary
Tissue damage triggers rapid recruitment of immune cells, with neutrophils as prime infiltrators [1, 2]. This migratory response marks the onset of inflammation, which is essential for protecting the breached tissue from infection while the slow process of tissue repair unfolds. Neutrophils are instrumental for killing bacterial pathogens through phagocytosis, release of proteolytic enzymes, and reactive radicals [1]. Prolonged neutrophil residence can cause collateral tissue damage, perpetuate inflammation, and delay tissue repair and restoration of homeostasis [1]. Tuning neutrophil accumulation to desirable levels is an important biomedical target, yet our basic understanding of how this response naturally escalates under physiological conditions remains limited
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