Orphan GPR84 facilitates uropod de-adhesion at multiple steps during leukocyte extravasation

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.