The LTB4 -BLT1 axis regulates the polarized trafficking of chemoattractant GPCRs during neutrophil chemotaxis

Journal of Cell Science
Bhagawat C SubramanianCarole A Parent

Abstract

Neutrophils sense and respond to diverse chemotactic cues through G-protein-coupled receptors (GPCRs). However, the precise trafficking dynamics of chemoattractant GPCRs during neutrophil activation and chemotaxis remain unclear. Here, by using small-molecule inhibitors and CRISPR-based knockouts, we establish that two primary chemoattractant GPCRs - formyl peptide receptor 1 (FPR1) and complement component 5a (C5a) receptor 1 (C5aR1) - internalize in a CDC42-actin-dependent manner. Through live-cell imaging, we demonstrate that, upon stimulation, FPR1 rapidly clusters and re-distributes along the plasma membrane to the trailing edge, where it internalizes and is directionally trafficked towards the front of migrating primary human neutrophils. In contrast to FPR1 and C5aR1, the leukotriene B4 (LTB4) receptor (BLT1, also known as LTB4R), which relays LTB4 signals in response to primary chemoattractants during neutrophil chemotaxis, fails to internalize upon physiological stimulation with LTB4, N-formyl-Met-Leu-Phe (fMLF) or C5a. Importantly, we report that blocking the LTB4-BLT1 axis or downstream myosin activation enhances the internalization of FPR1 and C5aR1, thus reducing downstream signaling and impairing chemotaxis to pri...Continue Reading

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Citations

Apr 3, 2020·Cellular & Molecular Immunology·Mieke MetzemaekersPaul Proost
Jul 1, 2020·Frontiers in Immunology·Heidi TackenbergTamás Laskay
Aug 28, 2020·The Journal of Cell Biology·Bhagawat C SubramanianCarole A Parent
Apr 30, 2021·Frontiers in Immunology·Shuvasree SenGuptaCarole A Parent
Jun 19, 2021·Science·Korbinian KienleTim Lämmermann
May 29, 2019·International Archives of Allergy and Immunology·Gilda VarricchiGianni Marone
Dec 30, 2021·The Journal of Cell Biology·Rachel M BrunettiOrion D Weiner

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