Understanding the chemokine scavenging function of C-C chemokine receptor type 2 (CCR2)

Migration of monocytes into tissues is driven by activation of the G protein-coupled receptor CCR2 in response to inflammatory chemokine CCL2 and is critical to normal immune responses. In addition to cell migration, CCR2 has a largely unappreciated scavenging function, by which it sequesters excess chemokine from the extracellular environment. We believe that this scavenging function allows CCR2 to control its own chemokine gradient, while its ability to recycle rather than downregulate allows it to maintain responsiveness in the presence of high chemokine concentration. Similarly, this function may be responsible for the difficulty observed when attempting to pharmacologically inhibit CCR2 activity. Therefore, an understanding of the molecular drivers underlying this chemokine scavenging is essential for developing effective therapeutics.Chemokine scavenging was widely regarded as a function of only atypical chemokine receptors (ACKRs), while scavenging by G protein coupled chemokine receptors has largely been ignored. In our soon to be published study (Chapter 1), we show that scavenging by CCR2 occurs in a manner independent of G proteins, G protein receptor kinases, arrestins, or clathrin, suggesting that a yet unknown non-canonical mechanism is largely responsible for this function. We therefore took a discovery-based approach using proximity labeling proteomics to further define the interactome of CCR2 along G protein-dependent and -independent pathways (Chapter 2). Finally, we discuss speculative, yet exciting, explanations of observations made in our latest findings and consider possible future experimental directions (Chapter 3). Collectively, the work presented herein highlights the complexity of CCR2 function, and significantly contributes to understanding and identifying the molecular drivers involved in chemokine scavenging