Control of murine Ly6Chigh monocyte traffic and immunosuppressive activities by atypical chemokine receptor D6

Abstract

The atypical chemokine receptor D6 is a decoy and scavenger receptor for most inflammatory CC chemokines and prevents the development of exacerbated inflammatory reactions. Here we report that mice lacking D6 expression in the nonhematopoietic compartment have a selective increase in the number of IntroductionThe chemokine system represents the main orchestrator of leukocyte recruitment. [1][2][3][4] Among several regulatory mechanisms, a prominent role has been recently recognized to a set of chemokine receptors indicated as atypical in that structurally unable to directly mediate cell migration. 5 Atypical chemokine receptors are structurally and functionally heterogeneous, but they share the biologic role of regulating signaling receptors' activity, by clearance, transport, or presentation of their cognate ligands. [5][6][7] D6 is one of these atypical chemokine receptors, and its main function is to bind and drive to degradation the majority of inflammatory CC chemokines. [8][9][10] By this chemokine scavenger function, D6 acts as a negative regulator of inflammation, as demonstrated by D6-deficient mice that are characterized by increased levels of inflammatory CC chemokines and development of exaggerated inflammatory reactions in different organs expressing D6 on lymphatic vessels, 11 including skin, 12,13 liver, 14 colon, 15,16 lungs, 17,18 and placenta, where its expression is restricted to trophoblast cells. 19 On the contrary, in certain conditions, the uncontrolled local inflammation observed in D6 Ϫ/Ϫ mice has been shown to impair the development of specific immune responses, protecting mice from development of autoimmune diseases. 20 Although D6 Ϫ/Ϫ mice have been investigated extensively, several aspects of D6 biology, including the precise mechanisms by which it regulates inflammatory responses, are not yet fully understood.In recent years, it became evident that inflammatory CC chemokines control not only monocyte recruitment at inflammatory sites but also regulate monocyte homeostasis and mobilization from the BM in infectious and hypercholesterolemia models. [21][22][23] Based on the expression of the myeloid differentiation antigen Ly6C and the chemokine receptors CCR2 and CX3CR1, 2 phenotypic and functional monocyte subsets have been described in mice. 24 Classic monocytes are Ly6C high /CCR2 ϩ /CX3CR1 low and are also called inflammatory monocytes because they produce high levels of TNF-␣ and IL-1␤ in inflamed tissues and lymph nodes (LNs) during infection or tissue damage. 25 The second subset is represented by nonclassic Ly6C Ϫ /CCR2 Ϫ /CX3CR1 high monocytes, also called patrolling monocytes because they crawl on the endothelium in homeostatic conditions, although they are the first extravasating cell type during an inflammatory response. 26 Interestingly, cells with classic monocyte phenotype are a component of the heterogeneous population of myeloid cells with immunoregulatory function called myeloid-derived suppressor cells (MDSCs). 27 This population consists of cells of myeloid ori...

Proinflammatory CX3CR1+CD59+Tumor Necrosis Factor–Like Molecule 1A+Interleukin‐23+ Monocytes Are Expanded in Patients With Ankylosing Spondylitis and Modulate Innate Lymphoid Cell 3 Immune Functions

“…[7] Mice lacking D6 expression in the nonhematopoietic compartment display a significant increase of pro-inflammatory monocytes in the peripheral blood and in secondary lymphoid tissues in a CCR2-dependent manner. [6] Thus the net CX3CR1 mediated immune response likely is affected by the balancing effects of CCL2 and D6.…”

“…[5] The trafficking of murine Ly6C + monocytes is regulated by the tissue expression of atypical chemokine receptor D6. [6] D6 is a decoy and scavenger receptor for most inflammatory CC chemokines, including CCL2, and helps prevent tissue inflammatory reactions. [7] Mice lacking D6 expression in the nonhematopoietic compartment display a significant increase of pro-inflammatory monocytes in the peripheral blood and in secondary lymphoid tissues in a CCR2-dependent manner.…”

Angiotensin-converting enzyme overexpression in myelomonocytes prevents Alzheimer’s-like cognitive decline

“…To assess the infiltration of blood-borne monocytic cells, we isolated and disassociated brains from age-matched 9.9-to 14.5-month-old AD + ACE WT/WT and AD + ACE 10/10 mice. We then studied resident and peripherally derived inflammatory cells by flow cytometry after antibody labeling for the immune surface markers CD45, CD11b, and Ly6C (49,50). Initial gating defined two populations: infiltrating hematopoietic cells (CD45 hi ) and microglia (CD11b + CD45 lo-intermed ) (Supplemental Figure 8A).…”

ERK-Dependent Downregulation of the Atypical Chemokine Receptor D6 Drives Tumor Aggressiveness in Kaposi Sarcoma

“…By targeting the degradation of most inflammatory CC chemokines and limiting their bioavailability in tissues, the atypical chemokine receptor D6 represents an emerging mechanism of regulation of the chemokine system (42). D6 has a well-established nonredundant role in the control of the inflammatory response, regulating the traffic and the activity of cells of the mononuclear system, in particular inflammatory monocytes (5), and also a negative role in inflammation-driven tumor development in experimental models (6,7). D6 has been reported to be expressed in human choriocarcinoma cell lines (43) and in breast (44) and vascular tumors (12,45), but its actual relevance in human cancer has not been established.…”

“…Besides these canonical receptors, which support chemotactic activity, there is a separate group of atypical chemokine receptors that do not directly mediate cell migration but are still involved in leukocyte recruitment as they participate in chemokine gradient formation by trapping, degrading, or transporting their ligands (3,4). D6 is an atypical chemokine receptor operating as a decoy and scavenger receptor for most inflammatory CC chemokines, and its role in the control of inflammatory responses is well established (3,5). D6-deficient mice have been reported to have increased susceptibility to skin carcinogenesis (6) and colitis-associated cancer (7), thus providing genetic evidence of a nonredundant function of inflammatory chemokines in tumor biology (8)(9)(10)(11).…”