Exosomes Mediate LTB(4) Release during Neutrophil Chemotaxis

Leukotriene B(4) (LTB(4)) is secreted by chemotactic neutrophils, forming a secondary gradient that amplifies the reach of primary chemoattractants. This strategy increases the recruitment range for neutrophils and is important during inflammation. Here, we show that LTB(4) and its synthesizing enzymes localize to intracellular multivesicular bodies that, upon stimulation, release their content as exosomes. Purified exosomes can activate resting neutrophils and elicit chemotactic activity in a LTB(4) receptor-dependent manner. Inhibition of exosome release leads to loss of directional motility with concomitant loss of LTB(4) release. Our findings establish that the exosomal pool of LTB(4) acts in an autocrine fashion to sensitize neutrophils towards the primary chemoattractant, and in a paracrine fashion to mediate the recruitment of neighboring neutrophils in trans. We envision that this mechanism is used by other signals to foster communication between cells in harsh extracellular environments.