Abstract
Chemokines and their receptors are key mediators of the inflammatory process regulating leukocyte extravasation and directional migration into inflamed and infected tissues. The control of chemokine availability within inflamed tissues is necessary to attain a resolving environment and when this fails chronic inflammation ensues. Accordingly, vertebrates have adopted a number of mechanisms for removing chemokines from inflamed sites to help precipitate resolution. Over the past 15 years, it has become apparent that essential players in this process are the members of the atypical chemokine receptor (ACKR) family. Broadly speaking, this family is expressed on stromal cell types and scavenges chemokines to either limit their spatial availability or to remove them from in vivo sites. Here, we provide a brief review of these ACKRs and discuss their involvement in the resolution of inflammatory responses and the therapeutic implications of our current knowledge.
Highlights
An effective inflammatory response requires carefully regulated initiation, maintenance, and resolution phases [1]
In the context of an inflammatory response, it is clear from a number of studies that numerous inflammatory chemokines are simultaneous expressed at damaged sites
Using ACKR4 in KO mice, it was demonstrated that homeostatic chemokine clearance is necessary to control excessive Th17 responses that can lead to immunopathologies [72]
Summary
An effective inflammatory response requires carefully regulated initiation, maintenance, and resolution phases [1]. Homeostatic chemokines are involved in the basal recruitment of cells involved in immune responses, and these control much more specific cellular navigation processes Chemokines interact with their target cells by binding to receptors belonging to the 7-transmembrane-spanning family of G protein-coupled receptors [6]. The formation of receptor dimers and oligomers at the cell surface can modify their chemokine binding and signaling activity, further complicating biology [7] This biological complexity, and the likely existence of biased-signaling in terms of receptor/ligand interactions [8, 9], suggests that chemokine receptor involvement in inflammatory responses is complex and potentially redundant. In the context of an inflammatory response, it is clear from a number of studies that numerous inflammatory chemokines are simultaneous expressed at damaged sites These attract leukocytes by interacting with inflammatory chemokine receptors and initiate inflammatory responses. We discuss the roles for ACKRs in the resolution of the inflammatory response and highlight their potential therapeutic value
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