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.
Highlights
NADPH oxidase-generated lyso-PS enhances efferocytosis by macrophages
Studies were initiated to explore the concept that lyso-PS generated in recruited neutrophils as a consequence of NADPH oxidase activation leads to an increase in “palatability” for uptake of these viable cells by macrophages
Because neutrophils lacking the NADPH oxidase are deficient in lyso-PS generation, these were compared with wild type cells in this analysis [16]
Summary
NADPH oxidase-generated lyso-PS enhances efferocytosis by macrophages. Results: Recruited, viable lyso-PShigh neutrophils are readily cleared by macrophages in vitro and in vivo via G2A signaling. Using neutrophils recruited to the peritoneum in a well characterized model of sterile peritonitis, it was shown that lyso-PS, a downstream product of the NADPH oxidative burst, drives the “early” recognition and clearance of viable and nonapoptotic neutrophils by macrophages via the process of efferocytosis, reprograms macrophages to a “resolving” state, and suppresses production of pro-inflammatory cytokines, including those implicated in neutrophil recruitment. These findings support the hypothesis that lyso-PS plays a pivotal role in calibration of tissue neutrophilia
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