The atypical chemokine receptor CCX-CKR scavenges homeostatic chemokines in circulation and tissues and suppresses Th17 responses

Abstract

Our previous in vitro studies led to proposals that the atypical chemokine receptor CCX-CKR is a scavenger of CCR7 ligand homeostatic chemokines. In the present study, we generated CCX-CKR ؊/؊ mice and confirm this scavenger function in vivo. Compared with wild-type mice, CCX-CKR ؊/؊ have a 5-fold increase in the level of CCL21 protein in blood, and 2-to 3-fold increases in CCL19 and CCL21 in peripheral lymph nodes. The effect of these protein increases on immunity was investigated after immunization with

β-Arrestin Recruitment and G Protein Signaling by the Atypical Human Chemokine Decoy Receptor CCX-CKR

“…CCX-CKR plays an important role in controlling the migration of immune and cancer cells that express chemokine receptors CCR7 and CCR9, by reducing the availability of CCL19, CCL21, and CCL25 through internalization (8,10,11,15). CCX-CKR internalization was previously found to be independent of ␤-arrestins and clathrin-coated pits, as dominantnegative ␤-arrestin, Eps15 and Rab5 mutants did not impair CCL19 internalization in CCX-CKR-expressing HEK293 cells (10).…”

“…Moreover, CCR7 and CCR9 have been shown to play a role in various cancers (9). CCX-CKR scavenges CCL19 and CCL21 both in vitro and in vivo, thereby decreasing the free concentration of these chemokines (7,8,10). Indeed, low CCX-CKR expression levels in breast cancer tumor cells were correlated with an increase in lymph node metastasis and consequently poor survival rate of patients (11).…”

“…CCL25, on the other hand, recruits antigen-experienced lymphocytes to the small intestine by activating CCR9 (6). Mouse CCX-CKR knock-out models demonstrated that CCX-CKR is important for steady-state homing of dendritic cells to skin-draining lymph nodes, T cell differentiation, and immune response kinetics in an experimental autoimmune encephalomyelitis model, by regulating local chemokine levels (7,8). Moreover, CCR7 and CCR9 have been shown to play a role in various cancers (9).…”

“…Additionally, CCX-CKR has been suggested to mediate CCL19 and CCL21 transcytosis across lymphatic endothelium, although direct evidence is still lacking (12). CCX-CKR is expressed in many tissues, including heart, lung, and intestine, as well as by stromal cells of skin-draining lymph nodes, thymic epithelial cells, and a number of hematopoietic cell types (4,7,8,(13)(14)(15)(16). Transgenic overexpression of CCX-CKR decreased hematopoietic precursor cell numbers in the thymic anlage at embryonic stages, whereas cell numbers returned to normal levels in newborn and adult mice (7).…”

The Role of Atypical Chemokine Receptor CCXCKR (CCRL1) in Human Diseases

“…51 By producing CCX-CKR -/-mice, Comerford et al confirmed the function of these receptors under in vivo conditions. 52 CCX-CKR -/-rats compared to wild-type ones demonstrated 5-fold increase in the blood levels of CCL21 protein, and 2 to 3 times increase in CCL19 and CCL21 chemokines in the peripheral lymph nodes. In experimental autoimmune encephalomyelitis model (EAE), in CCX-CKR -/-mice compared to wild type, the disease developed faster and more intense, which was associated with an increase in CCL21 in the central nervous system (CNS).…”