Atypical Chemokine Receptors in Renal Inflammation

Abstract

Chemokines are structurally related proteins which form a large family of chemotactic cytokines. They provide a general communication system for cells and regulate lymphocyte migration. These proteins orchestrate the formation of microenvironments in lymphoid tissue, promote lymphoid organogenesis and help foster vascular and lymphatic angiogenesis. In addition to the classical G proteincoupled chemokine receptors, many chemokines also bind to a family of nonsignaling proteins, now called interceptors (chemokine-internalizing proteins). Here we summarize recent data on the role of interceptors in chemokine biology with a focus on renal inflammation. Atypical Chemokine Receptors in Renal InflammationStephan Segerer a, b Jan Jedlicka a Rudolf P. Wüthrich As inflammatory cells migrate from the bloodstream, a chemokine signal is necessary for firm adhesion to the endothelium of venules. Therefore, chemokines need either to be expressed by endothelial cells, deposited on endothelial surfaces by platelets, or be transported through the endothelial layer, to be presented to passing leukocytes [4] . Having left the vessels, inflammatory cells travel through interstitial tissues most likely following haptotactic (matrix-bound) gradients towards the site of injury [3] . Defined structures of the extracellular matrix, particularly glycosaminoglycans and nonsignaling chemokine-binding proteins, are sites of chemokine presentation, and in the case of the interceptors, also transport [5] . These presenting structures change during inflammation [6] . Additionally, chemokine function is modified by the formation of dimers and multimers, occurring in the ligands and receptors [3] .An additional cascade of interactions between chemokines, soluble mediators, adhesion molecules and chemo- Key WordsChemokines ؒ Chemokine receptors ؒ Interceptors ؒ Nonsignaling receptor ؒ Duffy antigen/receptor for chemokines Abstract Chemokines are structurally related proteins which form a large family of chemotactic cytokines. They provide a general communication system for cells and regulate lymphocyte migration. These proteins orchestrate the formation of microenvironments in lymphoid tissue, promote lymphoid organogenesis and help foster vascular and lymphatic angiogenesis. In addition to the classical G protein-coupled chemokine receptors, many chemokines also bind to a family of nonsignaling proteins, now called interceptors (chemokine-internalizing proteins). Here we summarize recent data on the role of interceptors in chemokine biology with a focus on renal inflammation.

Protective role for CCR5 in murine lupus nephritis

“…Consecutives studies have clearly shown that the scavenging of chemokines by these atypical receptors plays an essential role in dampening inflammatory responses and induction of resolution (38). Whether chemokine consumption (i.e., binding-internalization-degradation) by classic "proinflammatory" chemokine receptors that do not belong to the nonsignaling family of scavenger receptors, such as CCR5, may be an additional mechanism for downregulation of the host's immune response is largely unknown (32).…”

The role of lymphatics in renal inflammation

“…Proteins expressed by LECs can directly modulate the local inflammatory milieu. The atypical chemokine receptor D6 takes up chemokines which results in digestion and local chemokine clearance [39,40]. The deletion of this receptor in mice leads to chronic inflammation of the skin [39].…”

Loss of Atypical Chemokine Receptors Expression Promotes Lymph Node Metastasis of Colorectal Cancer

“…In the chemokine system, a group of special receptors, called atypical chemokine receptors (ACKRs) or chemokine decoy receptors, recognize and bind the ligands without causing any signal transduction as they have the ability to capture the chemokines and to annihilated the signals [1][2]. Recently, three ACKRs, Duffy antigen receptor for chemokines (DARC or ACKR1), D6 (ACKR2) and ChemoCentryx chemokine receptor (CCX-CKR or ACKR4), have been widely concerned on their close associations with the occurrence and metastasis of tumors [3].…”