title: 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.
authors.affiliation: Department of Pediatrics, National Jewish Health, Denver, Colorado 80206, USA. fraschc@njhealth.org
authors.forename: S Courtney
authors.initials: SC
authors.lastname: Frasch
authors.forename: Ruby F
authors.initials: RF
authors.lastname: Fernandez-Boyanapalli
authors.forename: Karin A Zemski
authors.initials: KA
authors.lastname: Berry
authors.forename: Robert C
authors.initials: RC
authors.lastname: Murphy
authors.forename: Christina C
authors.initials: CC
authors.lastname: Leslie
authors.forename: Jerry A
authors.initials: JA
authors.lastname: Nick
authors.forename: Peter M
authors.initials: PM
authors.lastname: Henson
authors.forename: Donna L
authors.initials: DL
authors.lastname: Bratton
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D017209:Apoptosis; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D007249:Inflammation; D007960:Leukocyte Disorders / Q000151:congenital* / Q000378:metabolism; D008055:Lipids / Q000737:chemistry*; D008246:Lysophospholipids / Q000737:chemistry*; D008264:Macrophages / Q000166:cytology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019255:NADPH Oxidases / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology*; D016877:Oxidants / Q000737:chemistry*; D010538:Peritonitis / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D008055:Lipids; D008246:Lysophospholipids; D016877:Oxidants; C025059:lysophosphatidylserine; D019255:NADPH Oxidases