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

Abstract

Fetal loss in animals and humans is frequently associated with inflammatory conditions. D6 is a promiscuous chemokine receptor with decoy function, expressed in lymphatic endothelium, that recognizes and targets to degradation most inflammatory CC chemokines. Here, we report that D6 is expressed in placenta on invading extravillous trophoblasts and on the apical side of syncytiotrophoblast cells, at the very interface between maternal blood and fetus. Exposure of D6 ؊/؊ pregnant mice to LPS or antiphospholipid autoantibodies results in higher levels of inflammatory CC chemokines and increased leukocyte infiltrate in placenta, causing an increased rate of fetal loss, which is prevented by blocking inflammatory chemokines. Thus, the promiscuous decoy receptor for inflammatory CC chemokines D6 plays a nonredundant role in the protection against fetal loss caused by systemic inflammation and antiphospholipid antibodies.trophoblast ͉ leukocyte ͉ placenta

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).…”

“…Resolution is aided by D6, a 7TMR related to CCR1-5, which binds 12 of the chemokine ligands for these receptors (4,5) and is expressed, at least in humans, by lymphatic endothelial cells, trophoblasts, and some leukocyte populations (6,7). D6 null mice show prolonged exaggerated responses to cutaneous inflammatory stimuli and tumor induction (8 -10), enhanced leukocyte infiltration during allergic lung inflammation (11), and increased sensitivity to experimentally induced fetal resorption (7). Conversely, epidermal D6 transgene expression suppresses cutaneous inflammation and tumorigenesis (10).…”

Cutting Edge: Rapid Accumulation of Epidermal CCL27 in Skin-Draining Lymph Nodes following Topical Application of a Contact Sensitizer Recruits CCR10-Expressing T Cells

“…Data from several groups suggest that the decoy chemokine receptor D6 may a play critical role in controlling leukocyte infiltration by binding to and sequestering inflammatory chemokines in the skin, particularly those that bind to CCR1-5 (22). D6 is unlikely to sequester CCL27, however, because heterologous radioligand displacement experiments have suggested that D6 does not bind to CCL27 (R. Nibbs and G. Graham, unpublished observations).…”

Recognition Versus Adaptive Up-regulation and Degradation of CC Chemokines by the Chemokine Decoy Receptor D6 Are Determined by Their N-terminal Sequence

“…Ϫ/Ϫ mice have demonstrated that its chemokine scavenging activity attenuates the severity of inflammation in different experimental models (12,(15)(16)(17) and suppresses inflammation-driven tumor development (18) (19).…”

“…D6, the best described chemokine decoy receptor (6), is a constitutively internalizing receptor expressed by lymphatic endothelial cells (11), trophoblast cells (12), and, at lower levels, some leukocyte subsets (13). D6 selectively recognizes and degrades most inflammatory CC chemokine agonists of CCR1 to CCR5 (10).…”