Increased inflammation in mice deficient for the chemokine decoy receptor D6

Abstract

Chemokines are chemotactic cytokines with a key role in the control of cell trafficking and positioning under homeostatic and inflammatory conditions. D6 is a promiscuous 7-transmembrane-domain receptor expressed on lymphatic vessels which recognizes most inflammatory, but not homeostatic, CC chemokines. In vitro experiments demonstrated that D6 is unable to signal after ligand engagement, and it is structurally adapted to sustain rapid and efficient ligand internalization and degradation. These unique functional properties lead to the hypothesis that D6 may be involved in the control of inflammation by acting as a decoy and scavenger receptor for inflammatory chemokines. Consistent with this hypothesis, here we report that D6 -/-mice showed an anticipated and exacerbated inflammatory response in a model of skin inflammation. Moreover, the absence of D6 resulted in increase cellularity and inflammatorychemokine levels in draining lymph nodes. Thus, D6 is a decoy receptor structurally adapted and strategically located to tune tissue inflammation and control transfer of inflammatory chemokines to draining lymph nodes.

Multiple Roles for the C-terminal Tail of the Chemokine Scavenger D6

“…Thus, a simple model emerges whereby chemokine scavenging by D6 in vivo suppresses inflammatory leukocyte recruitment by reducing chemokine levels. Consistent with this model, elevated levels of bioavailable D6-binding chemokines are observed in inflamed D6 null mice (7)(8)(9)(10)(11).…”

Protection against inflammation- and autoantibody-caused fetal loss by the chemokine decoy receptor D6

“…Differently from other chemokine receptors, D6 expression has been reported mainly in nonhematopoietic cells and includes endothelial cells lining afferent lymphatic in certain anatomical sites, such as skin, gut, and lung (10). Evidence from genetargeted animals indicates that D6 plays a nonredundant role in the control of the local inflammatory response by acting as a decoy and scavenger receptor for inflammatory chemokines in the skin (11,12). D6 expression has also been detected in placenta (13), but its cellular location and function in this organ have not been previously investigated.…”

Tuning inflammation in tuberculosis: the role of decoy receptors

“…The increased recruitment of inflammatory cells in different organs of receptor-deficient mice may cause massive, local and systemic production of pro-inflammatory cytokines, such as TNFa and IL-1b and chemokines, which ultimately cause tissue damage, as suggested by date reported in the literature [47,49]. Accordingly, lung mononuclear cells from M. tuberculosisinfected D6 À/À and Tir8 À/À mice produced larger amounts of these cytokines, and, most important and relevant to the observed phenotype, abundantly higher levels of TNFa and IL-1b were found in bronchoalveolar lavage and sera of M. tuberculosis-infected D6-and Tir-8 deficient mice.…”

“…Several studies, reporting no signaling function but only a decoy activity for D6, were mainly addressed to the human molecule [7], although murine D6 owns the same structural features and functions as its human orthologue, acting as a silent receptor and efficient scavenger of inflammatory CC chemokines [47].…”

“…To investigate the role of this receptor in the resolution of murine inflammatory processes, different inflammation models were induced in D6-deficient mice (D6 À/À ), such as that locally occurring after subcutaneous injection of Complete Freund's adjuvant (CFA) [47], an emulsion of water in oil composed of inactivated and dried mycobacteria, usually M. tuberculosis, or after repeated applications of 12-O-tetradecanoyl phorbol-13-acetate (TPA), a tumor-promoting agent mutagenizing skin in murine models of cutaneous malignancy [48]. The first model of local inflammation was evaluated by histological analysis of the site of injection at earlier (3 days after CFA injection) and later (21 days after CFA injection) time points.…”