Orphan GPR84 facilitates uropod de-adhesion at multiple steps during leukocyte extravasation
5 affiliations
- 1Centre for Microvascular Research, William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London
- 2School of Biochemistry, Biomedical Sciences Building, University of Bristol
- 3Experimental Medicine and Rheumatology, William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London
- 4Institute of Cardiovascular Physiology and Pathophysiology, Biomedical Center, Ludwig-Maximilians-Universität München
- 5School of Cardiovascular and Metabolic Medicine and Sciences, James Black Centre, BHF Centre of Research Excellence, King’s College London
Abstract
Leukocyte migration through venular walls is an essential component of effective immunity. While the key molecular players driving the initial steps of this response are known, the terminating signals remain unclear. Here, we identify a conserved role for GPR84 family GPCRs in the successful completion of the final stages of leukocyte extravasation through acutely inflamed vessels. The integration of high-resolution intravital imaging with cell-specific genetics reveals that the deficiency of GPR84 orthologs in mice and Drosophila results in flawed detachment of transmigrating immune cells from vessel walls. Mechanistically, transcriptomics reveals that GPR84-deficient neutrophils exhibit defective actin cytoskeletal regulation and cellular adhesion/de-adhesion. Consistent with this, our fly-murine pipeline shows that GPR84 supports localized and dynamic Rho activation to enable detachment of the immune cell uropod from vessel exit sites. Moreover, pharmacological blockade of GPR84 signaling dampens immune cell migration in multiple murine acute inflammatory settings. Collectively, our findings present GPR84 as a novel physiological regulator of immune cell extravasation that is amenable to therapeutic targeting for modulating leukocyte infiltration into inflamed tissues.
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BibTeX
@article{latta2026orphan,
title = {{Orphan GPR84 facilitates uropod de-adhesion at multiple steps during leukocyte extravasation}},
author = {Clare Latta and Terrence M Trinca and Francesca Robertson and Rachel Lau and Anna Barkaway and Loïc Rolas and Matthew Golding and Paul R C Imbert and Haitao Wang and Almke Bader and Liam S Hill and Lorna Hodgson and Yue Yang and Aleksandar Ivetic and Barbara Walzog and Myles Lewis and Mathieu-Benoit Voisin and Paul Martin and Sussan Nourshargh and Helen Weavers},
journal = {EMBO Reports},
year = {2026},
month = sep,
doi = {10.1038/s44319-026-00923-0},
url = {https://doi.org/10.1038/s44319-026-00923-0},
note = {CC BY},
}
RIS
TY - JOUR
TI - Orphan GPR84 facilitates uropod de-adhesion at multiple steps during leukocyte extravasation
AU - Clare Latta
AU - Terrence M Trinca
AU - Francesca Robertson
AU - Rachel Lau
AU - Anna Barkaway
AU - Loïc Rolas
AU - Matthew Golding
AU - Paul R C Imbert
AU - Haitao Wang
AU - Almke Bader
AU - Liam S Hill
AU - Lorna Hodgson
AU - Yue Yang
AU - Aleksandar Ivetic
AU - Barbara Walzog
AU - Myles Lewis
AU - Mathieu-Benoit Voisin
AU - Paul Martin
AU - Sussan Nourshargh
AU - Helen Weavers
PY - 2026
DA - 2026/09/01
JO - EMBO Reports
DO - 10.1038/s44319-026-00923-0
UR - https://doi.org/10.1038/s44319-026-00923-0
AB - Leukocyte migration through venular walls is an essential component of effective immunity. While the key molecular players driving the initial steps of this response are known, the terminating signals remain unclear. Here, we identify a conserved role for GPR84 family GPCRs in the successful completion of the final stages of leukocyte extravasation through acutely inflamed vessels. The integration of high-resolution intravital imaging with cell-specific genetics reveals that the deficiency of GPR84 orthologs in mice and Drosophila results in flawed detachment of transmigrating immune cells from vessel walls. Mechanistically, transcriptomics reveals that GPR84-deficient neutrophils exhibit defective actin cytoskeletal regulation and cellular adhesion/de-adhesion. Consistent with this, our fly-murine pipeline shows that GPR84 supports localized and dynamic Rho activation to enable detachment of the immune cell uropod from vessel exit sites. Moreover, pharmacological blockade of GPR84 signaling dampens immune cell migration in multiple murine acute inflammatory settings. Collectively, our findings present GPR84 as a novel physiological regulator of immune cell extravasation that is amenable to therapeutic targeting for modulating leukocyte infiltration into inflamed tissues.
SN - 1469-3178
ER -