Neutrophils Regulate Tissue Neutrophilia in Inflammation via the Oxidant-modified Lipid Lysophosphatidylserine

Frasch, S. Courtney; Fernandez-Boyanapalli, Ruby; Berry, Karin A. Zemski; Murphy, Robert C.; Leslie, Christina C.; Nick, Jerry A.; Henson, Peter M.; Bratton, Donna L.

doi:10.1074/jbc.m112.438507

Cited by 49 publications

(39 citation statements)

References 55 publications

(86 reference statements)

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“…Interestingly, lyso-PS can be generated by two distinct pathways to influence phagocytosis; by cleavage of externalized PSox, as described herein by Lp-PLA 2 , or generated intracellularly via a NADPH oxidasedependent pathway by neutrophils. 53 There are currently no data implicating Lp-PLA 2 in the latter -that is, generation of intracellular lyso-PS by activated neutrophils.…”

Section: Resultsmentioning

confidence: 99%

Oxidatively modified phosphatidylserines on the surface of apoptotic cells are essential phagocytic ‘eat-me’ signals: cleavage and inhibition of phagocytosis by Lp-PLA2

et al. 2014

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Diversified anionic phospholipids, phosphatidylserines (PS), externalized to the surface of apoptotic cells are universal phagocytic signals. However, the role of major PS metabolites, such as peroxidized species of PS (PSox) and lyso-PS, in the clearance of apoptotic cells has not been rigorously evaluated. Here, we demonstrate that H 2 O 2 was equally effective in inducing apoptosis and externalization of PS in naive HL60 cells and in cells enriched with oxidizable polyunsaturated species of PS (supplemented with linoleic acid (LA)). Despite this, the uptake of LA-supplemented cells by RAW264.7 and THP-1 macrophages was more than an order of magnitude more effective than that of naive cells. A similar stimulation of phagocytosis was observed with LA-enriched HL60 cells and Jurkat cells triggered to apoptosis with staurosporine. This was due to the presence of PSox on the surface of apoptotic LA-supplemented cells (but not of naive cells). This enhanced phagocytosis was dependent on activation of the intrinsic apoptotic pathway, as no stimulation of phagocytosis occurred in LA-enriched cells challenged with Fas antibody. Incubation of apoptotic cells with lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ), a secreted enzyme with high specificity towards PSox, hydrolyzed peroxidized PS species in LA-supplemented cells resulting in the suppression of phagocytosis to the levels observed for naive cells. This suppression of phagocytosis by Lp-PLA 2 was blocked by a selective inhibitor of Lp-PLA 2 , SB-435495. Screening of possible receptor candidates revealed the ability of several PS receptors and bridging proteins to recognize both PS and PSox, albeit with diverse selectivity. We conclude that PSox is an effective phagocytic 'eat-me' signal that participates in the engulfment of cells undergoing intrinsic apoptosis.

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Section: Resultsmentioning

confidence: 99%

Oxidatively modified phosphatidylserines on the surface of apoptotic cells are essential phagocytic ‘eat-me’ signals: cleavage and inhibition of phagocytosis by Lp-PLA2

et al. 2014

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“…3), although the extent of the increase in CD36 was not as great as that observed in cases in which LysoPS works as a potent PPAR agonist. Other possible mechanisms for the LysoPS-mediated increase in oxLDL uptake include the augmentation of efferocytosis by LysoPS, and LysoPS reportedly enhances apoptotic cell engulfment by MPMs via G2A signaling 14) . However, since LysoPS did not increase the uptake of native LDL in this study, LysoPS may not simply increase the capacity of macrophages for phagocytosis, but rather increases the receptor-mediated oxLDL uptake.…”

Section: Discussionmentioning

confidence: 99%

“…After 24 hours, the total RNA of the cells was purified using the GenElute mammalian total RNA Miniprep kit (Sigma-Aldrich Co.) and LysoPS is thought to act as a potent lipid mediator, similar to LysoPA and S1P 9) . For example, LysoPS stimulates the degranulation of mast cells 10,11) , suppresses the proliferation of T lymphocytes 12) and induces apoptotic cell engulfment by macrophages 13,14) .…”

Section: Analysis Of the Gene Expression Using Real-time Rt-pcrmentioning

confidence: 99%

Lysophosphatidylserine has Bilateral Effects on Macrophages in the Pathogenesis of Atherosclerosis

Nishikawa

Kurano

Ikeda

et al. 2015

J Atheroscler Thromb

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“…Lysophosphatidylserine (lysoPS), a lipid exposed on apoptotic cells (particularly neutrophils) in a NADPH oxidase-dependent manner has been shown to enhance macrophage engulfment 166,167 . This may partly explain why patients with chronic granulomatous disease (CGD) that lack a functional NADPH oxidase have defects in apoptotic cell clearance and a hyper-inflammatory phenotype with a propensity for autoimmune disease 168 .…”

Section: Targeting Apoptotic Cell Clearance For Therapymentioning

confidence: 99%

Apoptotic cell clearance: basic biology and therapeutic potential

et al. 2014

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Prompt removal of apoptotic cells by phagocytes is important for maintaining tissue homeostasis. The molecular and cellular events that underpin apoptotic cell recognition and uptake, and the subsequent biological responses are increasingly better defined. The detection and disposal of apoptotic cells generally promote an anti-inflammatory response at the tissue level, as well as immunological tolerance. Consequently, defects in apoptotic cell clearance have been linked with a variety of inflammatory diseases and autoimmunity. Conversely, under certain conditions such as killing tumour cells by specific cell death inducers, the recognition of apoptotic tumour cells can promote an immunogenic response and anti-tumour immunity. Here, we review the current understanding of the complex process of apoptotic cell clearance in physiology and pathology, and discuss how this knowledge could be harnessed for new therapeutic strategies.

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Neutrophils Regulate Tissue Neutrophilia in Inflammation via the Oxidant-modified Lipid Lysophosphatidylserine

Cited by 49 publications

References 55 publications

Oxidatively modified phosphatidylserines on the surface of apoptotic cells are essential phagocytic ‘eat-me’ signals: cleavage and inhibition of phagocytosis by Lp-PLA2

Oxidatively modified phosphatidylserines on the surface of apoptotic cells are essential phagocytic ‘eat-me’ signals: cleavage and inhibition of phagocytosis by Lp-PLA2

Lysophosphatidylserine has Bilateral Effects on Macrophages in the Pathogenesis of Atherosclerosis

Apoptotic cell clearance: basic biology and therapeutic potential

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