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.
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Authors | S 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 |
Journal | The Journal of biological chemistry
(J Biol Chem)
Vol. 288
Issue 7
Pg. 4583-93
(Feb 15 2013)
ISSN: 1083-351X [Electronic] United States |
PMID | 23293064
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Anti-Inflammatory Agents
- Cytokines
- Lipids
- Lysophospholipids
- Oxidants
- lysophosphatidylserine
- NADPH Oxidases
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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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