CXCL17 is an endogenous inhibitor of CXCR4 via a novel mechanism of action

Abstract

CXCL17 is the most recently described chemokine. It is principally expressed by mucosal tissues, where it facilitates chemotaxis of monocytes, dendritic cells, and macrophages and has antimicrobial properties. CXCL17 is also implicated in the pathology of inflammatory disorders and progression of several cancers, as well as being highly upregulated during viral infections of the lung. However, the exact role of CXCL17 in health and disease is largely unknown, mainly due to a lack of known molecular targets mediating CXCL17 functional responses. Using a range of bioluminescence resonance energy transfer (BRET) based assays, here we demonstrate that CXCL17 inhibits CXCR4-mediated signalling and ligand binding. Moreover, CXCL17 interacts with neuropillin-1, a VEGFR2 co-receptor. Additionally, we find CXCL17 only inhibits CXCR4 ligand binding in intact cells and demonstrate that this effect is mimicked by known glycosaminoglycan binders, surfen and protamine sulfate. This indicates that CXCL17 inhibits CXCR4 by a unique mechanism of action that potentially requires the presence of a glycosaminoglycan containing accessory protein. Altogether, our results reveal that CXCL17 is an endogenous inhibitor of CXCR4 and represents an important discovery in our understanding of the (patho) physiological functions of CXCL17 and regulation of CXCR4 signalling.

CXCL17 binds efficaciously to glycosaminoglycans with the potential to modulate chemokine signaling

“…Indeed, at micromolar concentrations of CXCL17, we observed the disruption of chemotactic responses of CXCR1 transfectants to CXCL5, CXCL6, and CXCL8. A similar inhibitory observation was recently reported for the CXCL12–CXCR4 signaling axis ( 78 ), suggesting that CXCL17 may have broadly inhibitory effects on the function of a variety of chemokines and may serve to moderate chemokine signaling in vivo. This is also supported by our observations that chemotactic responses of CXCR6 transfectants to CXCL16 were also inhibited by the CXCL17 (24–119) form.…”

CXCL17 binds efficaciously to glycosaminoglycans with the potential to modulate chemokine signalling

“…We speculate that this may be due to competition for cell-surface GAGs on the migrating cell, or CXCL17 induced remodelling of the glycocalyx, since we have previously reported that GAG-binding is a requirement for chemotactic responses to CXCL8 [44]. A similar inhibitory observation was recently reported for the CXCL12-CXCR4 signalling axis [78], suggesting that CXCL17 may have broadly inhibitory effects on the function of a variety of chemokines and may serve to moderate chemokine signalling in vivo. A lack of such inhibition may explain in part, the perturbed trafficking of lymphoid and myeloid cells and exacerbated disease reported in CXCL17-deficient mice utilised in a model of experimental autoimmune encephalomyelitis (EAE) [79].…”

The cryptic role of CXCL17/CXCR8 axis in the pathogenesis of cancers: a review of the latest evidence

“…Moreover, It has been reported that CXCL17 can inhibit CXCR4‐mediated signaling and CXCL12 binding by mimicking protamine sulfate and surfen as glycosaminoglycan binders (White et al 2021). Considering the critical role of the CXCL12/CXCR4 axis in inducing proliferation and angiogenesis of tumor cells, CXCL17 as an endogenous CXCR4 inhibitor can play an anti‐tumor and protective role.…”

“…The distinctiveness of the receptor of CXCL17 is rather debated. Most studies recognize that CXCL17 has no binding affinity to CXCR2, CXCR3, CXCR4, CXCR7, CCR2, and CCR5 chemokine receptors CXCR8 (GPR35) as the receptor of this chemokine (Maravillas‐Montero et al 2015; White et al 2021). Previous studies have shown that calcium flux is increased in B cell line cells (Ba/F3) transfected with CXCR8, suggesting that downstream signaling pathways are initiated following the ligation of CXCL17 to CXCR8 (Maravillas‐Montero et al 2015).…”