Transcellular biosynthesis of leukotriene B4 orchestrates neutrophil swarming to fungi
Alex Hopke,
Tian Lin,
Allison K. Scherer,
Ashley E. Shay,
Kyle D. Timmer,
Brittany Wilson-Mifsud,
Michael K. Mansour,
Charles N. Serhan,
Daniel Irimia,
Bryan P. Hurley
Affiliations
Alex Hopke
Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Boston, MA 02129, USA; Harvard Medical School, Boston, MA 02115, USA; Shriners Hospital for Children, Boston, MA 02114, USA
Tian Lin
Harvard Medical School, Boston, MA 02115, USA; Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA 02114, USA
Allison K. Scherer
Harvard Medical School, Boston, MA 02115, USA; Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA 02114, USA
Ashley E. Shay
Harvard Medical School, Boston, MA 02115, USA; Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
Kyle D. Timmer
Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA 02114, USA
Brittany Wilson-Mifsud
Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA 02114, USA
Michael K. Mansour
Harvard Medical School, Boston, MA 02115, USA; Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA 02114, USA
Charles N. Serhan
Harvard Medical School, Boston, MA 02115, USA; Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
Daniel Irimia
Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Boston, MA 02129, USA; Harvard Medical School, Boston, MA 02115, USA; Shriners Hospital for Children, Boston, MA 02114, USA; Corresponding author
Bryan P. Hurley
Harvard Medical School, Boston, MA 02115, USA; Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA 02114, USA; Corresponding author
Summary: 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.
