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

Abstract

Atypical chemokine receptors (ACKRs) have emerged as important regulators or scavengers of homeostatic and inflammatory chemokines. Among these atypical receptors, ACKR4 is reported to bind the homeostatic chemokines CCL19, CCL21, CCL25 and CXCL13. In a recent study by Matti et al., the authors show that ACKR4 is also a receptor for CCL20, previously established to bind to CCR6 only. They provide convincing evidence that, just as for its other chemokine ligands, ACKR4 rapidly internalizes CCL20 both in vitro and in vivo. Independently of this discovery, we undertook a screening program aiming at reassessing the activity of the 43 human chemokines toward ACKR4 using a highly sensitive-arrestin recruitment assay. This systematic analysis confirmed CCL20 as a new agonist ligand for ACKR4 in addition to CCL19, CCL21, and CCL25. Furthermore, CCL22, which plays an important role in both homeostasis and inflammatory responses, and is known as a ligand for CCR4 and ACKR2 was found to also act as a potent partial agonist of ACKR4. In contrast, agonist activity of CXCL13 toward ACKR4 was disproved. This independent wide-range systematic study confirms the pairing of CCL20 with ACKR4 newly discovered by Matti and co-authors, and further refines the spectrum of chemokines activating ACKR4.

Mechanosensitive ACKR4 scavenges CCR7 chemokines to facilitate T cell de-adhesion and passive transport by flow in inflamed afferent lymphatics

“…Rather, ACKRs are typically expressed by stromal cells and impact leukocyte migration by transporting, presenting, or scavenging chemokines (Nibbs and Graham, 2013;Ulvmar et al, 2011). ACKR4 is one out of four so far described ACKRs and binds the CCR7 ligands, CCL19 and CCL21, as well as some further chemokines (i.e., CCL25 [Gosling et al, 2000], CCL20 [Matti et al, 2020a], and CCL22 [Meyrath et al, 2021]). Its function consists in binding and scavenging its ligands and submitting them to intracellular degradation (Nibbs and Graham, 2013).…”

New pairings and deorphanization among the atypical chemokine receptor family — physiological and clinical relevance

“…A parallel systematic pairing analysis using β-arrestin recruitment as readout confirmed CCL20 as a new full agonist ligand for ACKR4 with nanomolar potency ( 109 ). This study also found that CCL22 acts as a potent partial agonist of ACKR4.…”

Prospects for targeting ACKR1 in cancer and other diseases

“…ACKR3 expression has been described in a diversity of cell types with increasing evidence of ligand-specific, b-arrestin-mediated signaling pathways and multiple internalization mechanisms (17)(18)(19). ACKR4 binds CCL19, CCL20, CCL21, CCL22 and CCL25, a subset of chemokines associated with spatial organization of T-cells and dendritic cells (20). Knowledge of ACKR4 expression is incomplete, but it has been characterized as a component of endothelial barriers in tissues including the skin, spleen, and lymphatic vasculature and as a scavenger on fibroblasts in the dermis and intestinal submucosa (21)(22)(23).…”