Neutrophil swarming in damaged tissue is orchestrated by connexin-dependent calcium signals

Abstract

Neutrophils are major inflammatory cells that rapidly infiltrate injured tissues to provide antimicrobial functions. A key step in their response is the paracrine release of the attractant LTB4, which switches the migration mode from exploratory patrolling to coordinated swarming. This leads to dense clusters that may further disrupt tissue architecture. The coordination mechanism underpinning neutrophil swarms is elusive. Here we show that neutrophils swarms require mutual reinforcement of damage signalling 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 and sensing of the damage signal ATP. This 'calcium alarm' signal propagates in the nascent neutrophil cluster through connexin-43 hemichannels, which allow release of intracellular ATP. This enables rapid assembly of a centralised, supracellular chemoattractant source, which is instrumental for coordinated recruitment and maximal cell gathering.