A silent chemokine receptor regulates steady-state leukocyte homing in vivo

Abstract

The location of leukocytes in different microenvironments is intimately connected to their function and, in the case of leukocyte precursors, to the executed differentiation and maturation program. Leukocyte migration within lymphoid organs has been shown to be mediated by constitutively expressed chemokines, but how the bioavailability of these homeostatic chemokines is regulated remains unknown. Here, we report in vivo evidence for the role of a nonsignaling chemokine receptor in the migration of leukocytes under physiological, i.e., noninflammatory, conditions. We have studied the in vivo role of the silent chemokine receptor CCX-CKR1 by both loss-and gain-of-function approaches. CCX-CKR1 binds the constitutively expressed chemokines CC chemokine ligand (CCL)19, CCL21, and CCL25. We find that CCX-CKR1 is involved in the steady-state homing of CD11c ؉ MHCII high dendritic cells to skin-draining lymph nodes, and it affects the homing of embryonic thymic precursors to the thymic anlage. These observations indicate that the silent chemokine receptor CCX-CKR1, which is exclusively expressed by stroma cells, but not hematopoietic cells themselves, regulates homeostatic leukocyte migration by controlling the availability of chemokines in the extracellular space. This finding adds another level of complexity to our understanding of leukocyte homeostatic migration.cell trafficking ͉ homeostasis ͉ lymphopoiesis ͉ thymus

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

“…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).…”

CCRL1 marks heterogeneity in cortical and medullary thymic epithelial cells

“…In the thymus, CCRL1 is abundant in cTECs but not mTECs or thymocytes [20]. In fetal mice, CCRL1 regulates the migration of thymocyte precursors before vascularization [19]. It has been reported that CCRL1 deficiency results in thymus enlargement in adult mice, in association with altered thymocyte development and autoimmunity [21].…”

“…To do so, Ribeiro et al [18] analyze the expression of the atypical chemokine receptor CCRL1 during mouse ontogeny. It is known that CCRL1 (previously known as CCX-CKR or CCR11) is a nonsignaling scavenger receptor for the CC chemokine ligands CCL19, CCL21, and CCL25 [19]. In the thymus, CCRL1 is abundant in cTECs but not mTECs or thymocytes [20].…”