Journal
SCIENCE SIGNALING
Volume 14, Issue 673, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.aax3053
Keywords
-
Categories
Funding
- European Union's Horizon 2020 Research and Innovation Programme [779295]
- Hercules Foundation from the Flemish government [AKUL/11/31]
- FWO-Vlaanderen [G.0808.18N]
- C1 grant from KU Leuven [C16/17/10]
- FWO-Vlaanderen
- L'Oreal/UNESCO/FWO-Vlaanderen PhD scholarship
- H2020 Societal Challenges Programme [779295] Funding Source: H2020 Societal Challenges Programme
Ask authors/readers for more resources
CXCL5 interacts with CXCR2 and CXCR1 to activate neutrophils, and its N-terminal modifications can enhance its signaling effects. Additionally, CXCL5 can also attract monocytes, especially when the N-terminus is truncated.
The inflammatory human chemokine CXCL5 interacts with the G protein-coupled receptor CXCR2 to induce chemotaxis and activation of neutrophils. CXCL5 also has weak agonist activity toward CXCR1. The N-terminus of CXCL5 can be modified by proteolytic cleavage or deimination of Arg(9) to citrulline (Cit), and these modifications can occur separately or together. Here, we chemically synthesized native CXCL5(1-78), truncated CXCL5 [CXCL5(9-78)], and the citrullinated (Cit(9)) versions and characterized their functions in vitro and in vivo. Compared with full-length CXCL5, N-terminal truncation resulted in enhanced potency to induce G protein signaling and beta-arrestin recruitment through CXCR2, increased CXCL5-initiated internalization of CXCR2, and greater Ca2+ signaling downstream of not only CXCR2 but also CXCR1. Citrullination did not affect the capacity of CXCL5 to activate classical or alternative signaling pathways. Administering the various CXCL5 forms to mice revealed that in addition to neutrophils, CXCL5 exerted chemotactic activity toward monocytes and that this activity was increased by N-terminal truncation. These findings were confirmed by in vitro chemotaxis and Ca2+ signaling assays with primary human CD14(+) monocytes and human THP-1 monocytes. In vitro and in vivo analyses suggested that CXCL5 targeted monocytes through CXCR1 and CXCR2. Thus, truncation of the N-terminus makes CXCL5 a more potent chemoattractant for both neutrophils and monocytes that acts through CXCR1 and CXCR2.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available