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.
The engulfment of apoptotic leukocytes (efferocytosis) by macrophages during the resolution of inflammation is essential for homeostasis and results in macrophage reprogramming/immune-silencing. Here, we show CD11bhigh macrophages convert to CD11blow ones and stop efferocytosing apoptotic PMN after reaching an engulfment threshold in vivo. In addition, CD11blow macrophages are distinct from either M1 or M2 in their protein expression profile and display pro-resolving properties, such as diminished responses to different TLR ligands ex vivo and propensity to emigrate from resolving inflammation sites to lymphoid organs. Of interest, we found the pro-resolving lipid mediators resolvin E1 and D1, as well as the glucocorticoid dexamethasone (Dex) and the lectin galectin-1 enhance satiated-efferocytosis and consequently CD11blow macrophage conversion from their CD11bhigh counterparts. Deficiency in the atypical chemokine receptor D6 resulted in delayed satiation and reduced immune-silencing of macrophages, and inhibits their departure from resolving inflammation sites. In sum, satiated-efferocytosis is a novel phagocyte property of CD11blow macrophages that is regulated by pro-resolving mediators. Moreover, satiated-efferocytosis is required for CD11blow macrophage emigration from resolving inflammation sites and the return of tissue homeostasis. Thus, satiated-efferocytosis is essential for the completion of timely- and spatially-coordinated resolution of acute inflammation.
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