CCL20 is a novel ligand for the scavenging atypical chemokine receptor 4

Abstract

The chemokine CCL20 is broadly produced by endothelial cells in the liver, the lung, in lymph nodes and mucosal lymphoid tissues, and recruits CCR6 expressing leukocytes, particularly dendritic cells, mature B cells, and subpopulations of T cells. How CCL20 is systemically scavenged is currently unknown. Here, we identify that fluorescently labeled human and mouse CCL20 are efficiently taken-up by the atypical chemokine receptor ACKR4. CCL20 shares ACKR4 with the homeostatic chemokines CCL19, CCL21, and CCL25, although with a lower affinity. We demonstrate that all 4 human chemokines recruit -arrestin1 and -arrestin2 to human ACKR4. Similarly, mouse CCL19, CCL21, and CCL25 equally activate the human receptor. Interestingly, at the same chemokine concentration, mouse CCL20 did not recruit -arrestins to human ACKR4. Further cross-species analysis suggests that human ACKR4 preferentially takes-up human CCL20, whereas mouse ACKR4 similarly internalizes mouse and human CCL20. Furthermore, we engineered a fluorescently labeled chimeric chemokine consisting of the N-terminus of mouse CCL25 and the body of mouse CCL19, termed CCL25_19, which interacts with and is taken-up by human and mouse ACKR4. K E Y W O R D SACKR4, atypical chemokine receptor, CCL19, CCL20, CCL21, CCL25, chemokine scavenging, -arrestin

Systematic reassessment of chemokine-receptor pairings confirms CCL20 but not CXCL13 and extends the spectrum of ACKR4 agonists to CCL22

“…In a recent study, Matti and co‐authors reported CCL20, previously established to bind to CCR6 only, as a novel chemokine ligand for ACKR4 19 . The authors had predicted the existence of this interaction based on CCL20 sequence and expression similarities with CCL19 and CCL21.…”

“…Altogether, this systematic reassessment of chemokine-receptor interactions confirmed the pairing between CCL20 and ACKR4 in a different cellular background and using a different readout, 31 reinforcing the initial description by Matti and co-authors. 19 In addition, it identified another ligand for ACKR4, CCL22. These novel pairings add a level of complexity to ACKR4 interactions within the chemokine-receptor network and extend its regulatory functions to the CCL20/CCR6 and CCL22/CCR4 axes (Fig.…”

“…In a recent study, Matti and co-authors reported CCL20, previously established to bind to CCR6 only, as a novel chemokine ligand for ACKR4. 19 The authors had predicted the existence of this interaction based on CCL20 sequence and expression similarities with CCL19 and CCL21. They showed that CCL20 induces -arrestin-1 and -arrestin-2 recruitment to ACKR4, and is rapidly internalized and scavenged by ACKR4-expressing cells, both in vitro and in vivo.…”

“…They proposed that by scavenging CCL20, ACKR4 regulates its availability for the classical signaling receptor CCR6 and thereby plays a role in the positioning of CCR6-positive leukocytes within secondary lymphoid tissues to initiate effective humoral and memory immune responses. 19 Independently of this discovery, we undertook a systematic screening program aiming at reassessing the agonist activity of the 43 human chemokines (24 CCLs, 16 CXCLs, 2 XCLs, and 1 CX3CL) and 2 viral chemokines (vCCL1 and vCCL2) toward ACKR4, by monitoringarrestin recruitment to the receptor using a highly sensitive Nanoluciferase complementation-based assay (NanoBiT) (Fig. 1A).…”

Role of chemokines in hepatocellular carcinoma (Review)

“…ACKR2 can bind to and degrade all CC family chemokines, and ACKR3 is the scavenging receptor of CXC motif chemokine ligand 12 (CXCL12) and CXCL11, which serves a key role in tumor development (14). In addition, ACKR4 primarily scavenges CC motif chemokine ligand 19 (CCL19), CCL21 and CCL25 (15,16). Therefore, chemokines and their receptors can directly or indirectly shape the tumor cell microenvironment, and then affect the proliferation, invasion and metastasis of tumor cells.…”