Transcellular biosynthesis of leukotriene B4 orchestrates neutrophil swarming to fungi

Neutrophil swarming is an emergent host defense mechanism triggered by targets larger than a single neutrophil’s capacity to phagocytose. Swarming synergizes neutrophil functions, including chemotaxis, phagocytosis, and reactive oxygen species (ROS) production, and coordinates their deployment by many interacting neutrophils. The potent inflammatory lipid mediator leukotriene B4 (LTB4) has been established as central to orchestrating neutrophil activities during swarming. However, the details regarding how this eicosanoid choreographs the neutrophils involved in swarming are not well explained. Here we leverage microfluidics, genetically deficient mouse cells, and targeted metabolipidomic analysis to demonstrate that transcellular biosynthesis occurs among neutrophils to generate LTB4. Furthermore, transcellular biosynthesis is an entirely sufficient means of generating LTB4 for the purposes of orchestrating neutrophil swarming. These results further our understanding of how neutrophils coordinate their activities during swarming, which will be critical in the design of eventual therapies that can harness the power of swarming behavior. [Display omitted] •Mouse neutrophils unable to biosynthesize LTB4 fail to swarm or contain fungi•Exogenous LTB4 restores phagocytosis and ROS production but not swarming•Transcellular LTB4 biosynthesis restores swarming•Transcellular LTB4 biosynthesis controls fungal growth Immunology; Cell biology