The atypical chemokine receptor D6 controls macrophage efferocytosis and cytokine secretion during the resolution of inflammation.
The resolution of acute inflammation is hallmarked by the apoptotic death of inflammatory polymorphonuclear (PMN) cells, followed by their clearance by macrophages. In turn, resolution-phase macrophages exert reduced proinflammatory cytokine production, termed immune silencing. In this study, we found that the atypical chemokine receptor D6 plays an important and chemokine scavenging-independent role in promoting macrophage-mediated resolution. D6(-/-) mice displayed increased numbers of macrophages (2.2-fold increase), but not neutrophils, in their peritonea during the resolution of murine zymosan A-initiated peritonitis, in comparison to D6(+/+) animals. Moreover, D6-deficient macrophages engulfed higher numbers of apoptotic PMN cells in vivo (1.6-fold increase), and secreted higher amounts of TNF-α, CCL3, and CCL5 ex vivo than their wild-type (WT) counterparts. In addition, D6 was found to be expressed on apoptotic neutrophils from healthy humans and rodents. Moreover, the immune silencing of LPS-stimulated macrophages following their incubation with senescent PMN cells ex vivo (in terms of TNF-α, IL-1β, and CCL5 secretion) was diminished (50-65% decrease) when D6(-/-) PMN cells were applied. Accordingly, the adhesive responses induced by macrophage interactions with senescent PMN cells were reduced with D6-deficient PMN cells. Thus, our results indicate a novel mode of action for D6 during the resolution of inflammation that is instrumental to the shaping of resolving macrophage phenotypes and the completion of resolution.
Department of Biology, Faculty of Natural Sciences, University of Haifa, Haifa, Israel.
Ester
E
Pashover-Schallinger
Miran
M
Aswad
Sagie
S
Schif-Zuck
Haim
H
Shapiro
Pierre
P
Singer
Amiram
A
Ariel
D000818:Animals; D017209:Apoptosis; D016207:Cytokines / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism; D010538:Peritonitis / Q000378:metabolism / Q000503:physiopathology*; D054447:Receptors, CCR10 / Q000235:genetics / Q000502:physiology*; D000097628:Chemokine Receptor D6
D016207:Cytokines; D054447:Receptors, CCR10; D000097628:Chemokine Receptor D6