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Exosomes mediate LTB4 release during neutrophil chemotaxis.

ABSTRACT: Leukotriene B4 (LTB4) 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 LTB4 and its synthesizing enzymes localize to intracellular multivesicular bodies, which, upon stimulation, release their content as exosomes. Purified exosomes can activate resting neutrophils and elicit chemotactic activity in an LTB4 receptor-dependent manner. Inhibition of exosome release leads to loss of directional motility with concomitant loss of LTB4 release. Our findings establish that the exosomal pool of LTB4 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.

SUBMITTER: Majumdar R

PROVIDER: S-EPMC8262914 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Exosomes mediate LTB4 release during neutrophil chemotaxis.

Majumdar Ritankar R Tavakoli Tameh Aidin A Arya Subhash B SB Parent Carole A CA

PLoS biology 20210707 7

Leukotriene B4 (LTB4) 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 LTB4 and its synthesizing enzymes localize to intracellular multivesicular bodies, which, upon stimulation, release their content as exosomes. Purified exosomes can activate resting neutrophils and elicit chemotactic activity in an LTB4 ...[more]

PMID: 34232954

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Project description:Neutrophils are always surrounded by/interacting with other components of the immune system; however, the current mechanistic understanding of neutrophil function is largely based on how neutrophils respond to a single chemical signal in a simplified environment. Such approaches are unable to recapitulate the in vivo microenvironment; thus, cell behavior may not fully represent the physiological behavior. Herein, we exploit a microfluidic model of the complex in vivo milieu to investigate how cell-cell interactions influence human neutrophil migration and surface marker expression. Neutrophil migration against a bacterially derived chemoattractant (formyl-met-leu-phe, fMLP), with and without preactivation by interleukins (interleukin-2 or interleukin-6), was evaluated in the presence and absence of endothelial support cells. Preactivation by interleukins or interaction with endothelial cells resulted in altered migration rates compared to naïve neutrophils, and migration trajectories deviated from the expected movement toward the fMLP signal. Interestingly, interaction with both interleukins and endothelial cells simultaneously resulted in a slight compensation in the deviation-on endothelial cells, 34.4% of untreated neutrophils moved away from the fMLP signal, while only 15.2 or 22.2% (interleukin-2-or interleukin-6-activated) of preactivated cells moved away from fMLP. Neutrophils interacting with interleukins and/or endothelial cells were still capable of prioritizing the fMLP signal over a competing chemoattractant, leukotriene B4 (LTB4). Fluorescence imaging of individual human neutrophils revealed that neutrophils treated with endothelial-cell-conditioned media showed up-regulation of the surface adhesion molecules cluster determinant 11b and 66b (CD11b and CD66b) upon stimulation. On the other hand, CD11b and CD66b down-regulation was observed in untreated neutrophils. These results leverage single cell analysis to reveal that the interaction between neutrophils and endothelial cells is involved in surface marker regulation and thus chemotaxis of neutrophils. This study brings new knowledge about neutrophil chemotaxis in the context of cell-to-cell communications, yielding both fundamental and therapeutically relevant insight.

Dataset Information

Exosomes mediate LTB4 release during neutrophil chemotaxis.

Publications

Exosomes mediate LTB4 release during neutrophil chemotaxis.

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