Atypical chemokine receptor ACKR2 controls branching morphogenesis in the developing mammary gland.

Macrophages are important regulators of branching morphogenesis during development and postnatally in the mammary gland. Regulation of macrophage dynamics during these processes can therefore have a profound impact on development. We demonstrate here that the developing mammary gland expresses high levels of inflammatory CC-chemokines, which are essential in vivo regulators of macrophage migration. We further demonstrate that the atypical chemokine receptor ACKR2, which scavenges inflammatory CC-chemokines, is differentially expressed during mammary gland development. We have previously shown that ACKR2 regulates macrophage dynamics during lymphatic vessel development. Here, we extend these observations to reveal a novel role for ACKR2 in regulating the postnatal development of the mammary gland. Specifically, we show that Ackr2-/- mice display precocious mammary gland development. This is associated with increased macrophage recruitment to the developing gland and increased density of the ductal epithelial network. These data demonstrate that ACKR2 is an important regulator of branching morphogenesis in diverse biological contexts and provide the first evidence of a role for chemokines and their receptors in postnatal development processes.

Cell-autonomous regulation of neutrophil migration by the D6 chemokine decoy receptor.

Chemokines, acting on their cognate receptors on infiltrating leukocytes, drive the inflammatory response. We have been interested in determining roles and potential mechanisms for the atypical chemokine-scavenging receptor D6 in the regulation of inflammation. In this study, we show that a psoriasis-like pathology that arises in inflamed skins of D6-deficient mice is characterized by a massive and aberrant localization of neutrophils to the dermal/epidermal junction, which is associated with development of the pathology. Such misplacement of neutrophils is also seen with D6-deficient mice in other inflammatory models, suggesting a role for D6 in the spatial positioning of neutrophils within inflamed sites. We further show that D6 functions cell autonomously in this context and that D6, expressed by neutrophils, limits their migrational responses to CCR1 ligands such as CCL3. Our data therefore indicate that D6 is able to play a cell-autonomous role as a migratory rheostat restricting migration of D6-expressing cells such as neutrophils toward ligands for coexpressed inflammatory chemokine receptors. These data have important implications for our understanding of the roles for D6 in regulating inflammation and for our understanding of the control of spatial positioning of leukocytes at inflamed sites.

D6 facilitates cellular migration and fluid flow to lymph nodes by suppressing lymphatic congestion.

Lymphatic endothelial cells are important for efficient flow of antigen-bearing fluid and antigen-presenting cells (APCs) from peripheral sites to lymph nodes (LNs). APC movement to LNs is dependent on the constitutive chemokine receptor CCR7, although how conflicting inflammatory and constitutive chemokine cues are integrated at lymphatic surfaces during this process is not understood. Here we reveal a previously unrecognized aspect of the regulation of this process. The D6 chemokine-scavenging receptor, which is expressed on lymphatic endothelial cells (LECs), maintains lymphatic surfaces free of inflammatory CC-chemokines and minimizes interaction of inflammatory leukocytes with these surfaces. D6 does not alter the level of CCR7 ligands on LECs, thus ensuring selective presentation of homeostatic chemokines for interaction with CCR7(+) APCs. Accordingly, in D6-deficient mice, inflammatory CC-chemokine adherence to LECs results in inappropriate perilymphatic accumulation of inflammatory leukocytes at peripheral inflamed sites and draining LNs. This results in lymphatic congestion and impaired movement of APCs, and fluid, from inflamed sites to LNs. We propose that D6, by suppressing inflammatory chemokine binding to lymphatic surfaces, and thereby preventing inappropriate inflammatory leukocyte adherence, is a key regulator of lymphatic function and a novel, and indispensable, contributor to the integration of innate and adaptive immune responses.