Self-extinguishing relay waves enable homeostatic control of human neutrophil swarming.

Robert Insall

Robert Insall

Robert Insall

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Neutrophils have been the subject of choice for chemotaxis studies since the heady work of Sally Zigmond in the 1970s. Recently, however, things have become more complex - Zigmond painted a simple story in which cells simply respond to external gradients, but a number of researchers noticed that in some experiments the neutrophils swarm together; this indicates that they respond dynamically to one another, as well as to external signals in the environment. One key molecule is the lipid leukotriene B4 (LTB4 {1}).

Strickland et al. now follow the LTB4 message passing between individual cells (indirectly, inferred from calcium signalling within the cells, but very clearly). They reveal that the information passes in waves, with an initial stimulus caused by a pathogen, but nearly all neutrophils responding indirectly to LTB4 from their neighbours rather than to the pathogen itself. That is to say, the signal is "relayed" from cell to cell. The direction of movement is always towards the pathogen, but the chemoattractant is LTB4 for most cells. In this sense, neutrophils turn out to be like another well-studied chemotactic cell, Dictyostelium; the principal difference is the initiating stimulus, which is distinct in neutrophils (Candida initiates in this work, but LTB4 propagates) but the stimulus and the relay are the same for Dictyostelium.

Strickland et al. then show that the waves are limited by a mechanism that breaks down the LTB4, using the intracellular NADPH oxidase complex, which is highly expressed in neutrophils. This restricts the wave to a particular group of cells, and tunes the response; in Dictyostelium, by contrast, the waves can extend over arbitrary distances, and the aggregate sizes are limited only because of competition between many points of initiation. It also means that LTB4 chemotaxis is complex - cells shape the gradients as they respond to them, making them steeper or too shallow to read - although the initial direct comes from the Candida, the gradients are shaped by self-generated gradients {2}, with neutrophils both making and breaking LTB4 in a wildly dynamic way.