Search

Purpose: To re-evaluate the role of the atypical chemokine receptor-2 (ACKR2) in corneal graft rejection and investigate the effect of ACKR2 on inflammation-associated lymphangiogenesis using murine orthotopic corneal transplantation.Methods: Corneal grafts were performed and evaluated in the settings of syngeneic, allogeneic and single antigen (HY-antigen) disparity pairings. Corneal vessels were quantified in whole mounts from WT, ACKR2−/− and F4/80−/−ACKR2−/− mice that received syngeneic or allogeneic grafts using anti-CD31 and anti-Lyve-1 antibodies.Results: Syngeneic corneal grafts in WT and ACKR2−/− mice were 100% accepted. Fully histo-incompatible allogeneic grafts were rapidly rejected (100%) with similar tempo in both WT and ACKR2−/− hosts. Around 50% of single-antigen (HY) disparity grafts rejected at a slow but similar tempo (60 days) in WT and ACKR2−/− mice. Prior to grafting, F4/80−/−ACKR2−/− mice had lower baseline levels of limbal blood and lymphatic vessels compared to ACKR2−/− mice. Syngeneic grafts, but not allogeneic grafts, in ACKR2−/− and F4/80−/−ACKR2−/− mice induced higher levels of lymphatic sprouting and infiltration of Lyve-1+ cells during the early (3d) post-graft (pg) stage but lymphatic density was similar to WT grafted mice by 7d pg.Conclusions: Our results indicate that the chemokine scavenger receptor, ACKR2, has no role to play in the survival of allogeneic grafts. A minor role in regulation of lymphangiogenesis in the early stage of wound healing in syngeneic grafts is suggested, but this effect is probably masked by the more pronounced lymphangiogenic inflammatory response in allogeneic grafts. No additional effect was observed with the deletion of the resident macrophage gene, F4/80. [ABSTRACT FROM AUTHOR]

Chemokines have fundamental roles in regulating immune and inflammatory responses, primarily through their control of leukocyte migration and localization. The biological functions of chemokines are typically mediated by signalling through G protein-coupled chemokine receptors, but chemokines are also bound by a small family of atypical chemokine receptors (ACKRs), the members of which are unified by their inability to initiate classical signalling pathways after ligand binding. These ACKRs are emerging as crucial regulatory components of chemokine networks in a wide range of developmental, physiological and pathological contexts. In this Review, we discuss the biochemical and immunological properties of ACKRs and the potential unifying themes in this family, and we highlight recent studies that identify novel roles for these molecules in development , homeostasis, inflammatory disease, infection and cancer. [ABSTRACT FROM AUTHOR]

The Duffy antigen receptor for chemokines (DARC) belongs to a family of 'silent' heptahelical chemokine receptors that do not couple to G proteins and fail to transmit measurable intracellular signals. DARC binds most inflammatory chemokines and is prominently expressed on venular endothelial cells, where its function has remained contentious. Here we show that DARC, like other silent receptors, internalized chemokines but did not effectively scavenge them. Instead, DARC mediated chemokine transcytosis, which led to apical retention of intact chemokines and more leukocyte migration across monolayers expressing DARC. Mice overexpressing DARC on blood vessel endothelium had enhanced chemokine-induced leukocyte extravasation and contact-hypersensitivity reactions. Thus, interactions of chemokines with DARC support their activity on apposing leukocytes in vitro and in vivo. [ABSTRACT FROM AUTHOR]

How the inflammatory response is initiated has been well defined but relatively little is known about how such responses are resolved. Here we show that the D6 chemokine receptor is involved in the post-inflammatory clearance ofß-chemokines from cutaneous sites. After induction of inflammation by phorbol esters, wild-type mice showed a transient inflammatory response. However, in D6-deficient mice, an excess concentration of residual chemokines caused a notable inflammatory pathology with similarities to human psoriasis. These results suggest that D6 is involved in the resolution of the cutaneous inflammatory response. [ABSTRACT FROM AUTHOR]

CXCR2 is an essential regulator of neutrophil recruitment to inflamed and damaged sites and plays prominent roles in inflammatory pathologies and cancer. It has therefore been highlighted as an important therapeutic target. However the success of the therapeutic targeting of CXCR2 is threatened by our relative lack of knowledge of its precise in vivo mode of action. Here we demonstrate that CXCR2-deficient mice display a counterintuitive transient exaggerated inflammatory response to cutaneous and peritoneal inflammatory stimuli. In both situations, this is associated with reduced expression of cytokines associated with the resolution of the inflammatory response and an increase in macrophage accumulation at inflamed sites. Analysis using neutrophil depletion strategies indicates that this is a consequence of impaired recruitment of a non-neutrophilic CXCR2 positive leukocyte population. We suggest that these cells may be myeloid derived suppressor cells. Our data therefore reveal novel and previously unanticipated roles for CXCR2 in the orchestration of the inflammatory response. [ABSTRACT FROM AUTHOR]