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- Title
Endogenous modification of the chemoattractant CXCL5 alters receptor usage and enhances its activity toward neutrophils and monocytes.
- Authors
Metzemaekers, Mieke; Mortier, Anneleen; Vacchini, Alessandro; Boff, Daiane; Yu, Karen; Janssens, Rik; Farina, Floriana M.; Milanesi, Samantha; Berghmans, Nele; Pörtner, Noëmie; Van Damme, Jo; Allegretti, Marcello; Teixeira, Mauro M.; Locati, Massimo; Borroni, Elena M.; Amaral, Flavio A.; Proost, Paul
- Abstract
Truncation-enhanced agonism: The chemokine CXCL5 stimulates inflammation by recruiting and activating neutrophils through the G protein–coupled receptor CXCR2. Human CXCL5 is posttranslationally modified by N-terminal truncation and citrullination. Metzemaekers et al. compared the activities of full-length, unmodified CXCL5 with forms of CXCL5 that were truncated, citrullinated, or both. Whereas citrullination did not affect CXCL5-dependent signal transduction or chemotaxis, N-terminal truncation enhanced CXCL5-induced intracellular signaling downstream of CXCR1 and CXCR2 and promoted chemotaxis of mouse and human monocytes. Truncation also enhanced CXCL5-mediated recruitment of neutrophils and monocytes into the knee joints of mice unless the mice were treated with an antagonist specific for CXCR1 and CXCR2. Thus, naturally occurring proteolytic modifications affect the potency of CXCL5 for stimulating intracellular responses and, consequently, the recruitment of neutrophils and monocytes. 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 Arg9 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 (Cit9) 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 β-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.
- Subjects
MONOCYTES; CHEMOTAXIS; NEUTROPHILS; G protein coupled receptors; G proteins; KNEE; CELLULAR signal transduction
- Publication
Science Signaling, 2021, Vol 14, Issue 673, p1
- ISSN
1945-0877
- Publication type
Article
- DOI
10.1126/scisignal.aax3053