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Neutrophils regulate tissue Neutrophilia in inflammation via the oxidant-modified lipid lysophosphatidylserine.

Abstract
Resolution of neutrophilia characteristic of acute inflammation requires cessation of neutrophil recruitment and removal of tissue neutrophils. Based on in vitro studies, a role in these events was hypothesized for oxidant-generated lysophosphatidylserine (lyso-PS) on recruited neutrophils signaling via the G2A receptor on macrophages. Peritoneal exudate neutrophils harvested from wild type (WT) mice had 5-fold more lyso-PS (lyso-PS(high)) than those of gp91(phox)(-/-) (lyso-PS(low)) mice. Ex vivo engulfment of lyso-PS(high) neutrophils (95% viable) by WT peritoneal macrophages was quantitatively similar to UV-irradiated apoptotic blood neutrophils, although the signaling pathway for the former was uniquely dependent on macrophage G2A. In contrast, lyso-PS(low) neutrophils were poorly engulfed unless presented with exogenous lyso-PS. Enhanced clearance of lyso-PS(high) neutrophils was also seen in vivo following their adoptive transfer into inflamed peritonea of WT but not G2A(-/-) mice, further supporting a requirement for signaling via G2A. To investigate downstream effects of lyso-PS/G2A signaling, antibody blockade of G2A in WT mice reduced macrophage CD206 expression and efferocytosis during peritonitis. Conversely, adoptive transfer of lyso-PS(high) neutrophils early in inflammation in gp91(phox)(-/-) mice led to accelerated development of efferocytic(high) and CD206(high) macrophages. This macrophage reprogramming was associated with suppressed production of pro-inflammatory mediators and reduced neutrophilia. These effects were not seen if G2A was blocked or lyso-PS(low) neutrophils were transferred. Taken together, the results demonstrate that oxidant-generated lyso-PS made by viable tissue neutrophils is an endogenous anti-inflammatory mediator working in vivo to orchestrate the "early" and rapid clearance of recruited neutrophils as well as the reprogramming of "resolving" macrophages.
AuthorsS Courtney Frasch, Ruby F Fernandez-Boyanapalli, Karin A Zemski Berry, Robert C Murphy, Christina C Leslie, Jerry A Nick, Peter M Henson, Donna L Bratton
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 288 Issue 7 Pg. 4583-93 (Feb 15 2013) ISSN: 1083-351X [Electronic] United States
PMID23293064 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Anti-Inflammatory Agents
  • Cytokines
  • Lipids
  • Lysophospholipids
  • Oxidants
  • lysophosphatidylserine
  • NADPH Oxidases
Topics
  • Animals
  • Anti-Inflammatory Agents (pharmacology)
  • Apoptosis
  • Cytokines (metabolism)
  • Disease Models, Animal
  • Female
  • Inflammation
  • Leukocyte Disorders (congenital, metabolism)
  • Lipids (chemistry)
  • Lysophospholipids (chemistry)
  • Macrophages (cytology)
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • NADPH Oxidases (metabolism)
  • Neutrophils (cytology)
  • Oxidants (chemistry)
  • Peritonitis (metabolism)
  • Signal Transduction

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