Modulation of Neutrophil Apoptosis and the Resolution of Inflammation through β2 Integrins - PubMed (original) (raw)

Modulation of Neutrophil Apoptosis and the Resolution of Inflammation through β2 Integrins

Driss El Kebir et al. Front Immunol. 2013.

Abstract

Precise control of the neutrophil death program provides a balance between their defense functions and safe clearance, whereas impaired regulation of neutrophil death is thought to contribute to a wide range of inflammatory pathologies. Apoptosis is essential for neutrophil functional shutdown, removal of emigrated neutrophils, and timely resolution of inflammation. Neutrophils receive survival and pro-apoptosis cues from the inflammatory microenvironment and integrate these signals through surface receptors and common downstream mechanisms. Among these receptors are the leukocyte-specific membrane receptors β2 integrins that are best known for regulating adhesion and phagocytosis. Accumulating evidence indicate that outside-in signaling through the β2 integrin Mac-1 can generate contrasting cues in neutrophils, leading to promotion of their survival or apoptosis. Binding of Mac-1 to its ligands ICAM-1, fibrinogen, or the azurophilic granule enzyme myeloperoxidase suppresses apoptosis, whereas Mac-1-mediated phagocytosis of bacteria evokes apoptotic cell death. Mac-1 signaling is also target for the anti-inflammatory, pro-resolving mediators, including lipoxin A4, aspirin-triggered lipoxin A4, and resolvin E1. This review focuses on molecular mechanisms underlying Mac-1 regulation of neutrophil apoptosis and highlights recent advances how hierarchy of survival and pro-apoptosis signals can be harnessed to facilitate neutrophil apoptosis and the resolution of inflammation.

Keywords: Mac-1; apoptosis; lipoxins; myeloperoxidase; neutrophils; phagocytosis; resolution of inflammation; resolvins.

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Figures

Figure 1

Figure 1

Contrasting outside-in signals through Mac-1 modulates survival and death decision in neutrophils. Aging neutrophils undergo constitutive apoptosis triggered by collapse of mitochondrial function. Engagement of Mac-1 with its ligands ICAM-1, fibrinogen, or MPO delays apoptosis by generating survival cues through activation of the PI3K/Akt and MEK/ERK pathways. Additional stimulation of death receptors with TNF or FasL evokes release of ROS, which through activation of lyn and SHIP leads to inhibition of Akt. Mac-1-mediated phagocytosis of opsonized bacteria evokes ROS production by NADPH oxidase, leading to ROS-mediated activation of caspase-8 and inhibition of ERK, and acceleration of the cell death program. Apoptotic neutrophils are recognized and phagocytosed by macrophages (efferocytosis), thus contributing to inflammatory resolution. Extended neutrophil longevity contributes to aggravation and prolongation of the inflammatory response.

Figure 2

Figure 2

Myeloperoxidase (MPO)-Mac-1 self-amplifying circuit promotes neutrophils survival and inflammation. MPO binding to Mac-1 results in p38 MAPK-mediated NADPH oxidase, and PI3K/Akt and MEK/ERK-mediated preservation of the anti-apoptotic protein Mcl-1, leading to suppression of apoptosis. MPO also triggers MPO release from the azurophilic granules, and upregulates Mac-1 expression, thereby forming an autocrine/paracrine self-amplifying circuit. MPO catalyzed formation of HOCl, activation of NF-κB-regulated transcription of pro-inflammatory genes, recruitment of neutrophils, and prolongation of neutrophil longevity contribute to tissue damage and inflammation.

Figure 3

Figure 3

Multipronged actions of lipoxins to inhibit the myeloperoxidase (MPO)-Mac-1 circuit. Lipoxin A4 (LXA4) and aspirin-triggered 15-epi-LXA4 predominantly through FPR2/ALX attenuate MPO-stimulated degranulation, upregulation of surface expression of Mac-1, and superoxide formation, thus effectively interrupting this loop. LXA4 and15-epi-LXA4 redirect neutrophils to apoptosis by overriding the powerful survival signals from MPO through inducing loss of expression of Mcl-1 and aggravating mitochondrial dysfunction. Lipoxins also enhance phagocytosis of apoptotic neutrophils by macrophages.

Figure 4

Figure 4

Therapeutic induction of neutrophil apoptosis with demonstrated pro-resolution actions in vivo. Treatment of experimental animals with CDK inhibitor drugs (e.g., R-roscovitine), 15-epi-LXA4, RvE1, rTRAIL, or annexin A1 enhance the resolution of inflammation by promoting apoptosis of neutrophils that have emigrated into tissues in various models of inflammation. Roscovitine through yet unidentified mechanisms, 15-epi-LXA4 through attenuating MPO-triggered Mac-1-mediated survival signaling and annexin A1 through dampening intracellular survival signaling down-regulate expression of the key survival protein Mcl-1. RvE1 enhances phagocytosis-induced apoptosis, leading to activation of caspase-8 and suppression of Mcl-1.rTRAIL activates caspase-8.

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