The atypical chemokine receptor D6 controls macrophage efferocytosis and cytokine secretion during the resolution of inflammation

Ester Pashover-Schallinger, Miran Aswad, Sagie Schif-Zuck, Haim Shapiro, Pierre Singer, Amiram Ariel

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)3891-3900
Number of pages10
JournalFASEB Journal
Volume26
Issue number9
DOIs
StatePublished - Sep 2012
Externally publishedYes

Keywords

  • Acute immune responses
  • Apoptotic cell clearance
  • Chemokine receptors
  • Leukocytes

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