Macrophages Survive Hyperoxia via Prolonged ERK Activation Due to Phosphatase Down-regulation

Nyunoya, Toru; Monick, Martha M.; Powers, Linda S.; Yarovinsky, Timur O.; Hunninghake, Gary W.

doi:10.1074/jbc.m500185200

Cited by 31 publications

(33 citation statements)

References 53 publications

(53 reference statements)

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“…For example, ERK has been reported to be an important macrophage survival factor in some (35)(36)(37)(38)(39)(40) but not all (30,41,42) studies, and we detected decreased ERK phosphorylation in response to LPS or thapsigargin in BMDMs from both WT and BCAP-deficient mice, as well as a trend for enhanced ERK phosphorylation in unchallenged BMDMs from BCAP-deficient mice (Fig. 4).…”

Section: Bcap Is Required For Maximal Activation Of Akt In Response Tsupporting

confidence: 50%

A Requirement for the p85 PI3K Adapter Protein BCAP in the Protection of Macrophages from Apoptosis Induced by Endoplasmic Reticulum Stress

Song

Chew

Dale

et al. 2011

The Journal of Immunology

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Macrophages are innate immune cells that play key roles in regulation of the immune response and in tissue injury and repair. In response to specific innate immune stimuli, macrophages may exhibit signs of endoplasmic reticulum (ER) stress and progress to apoptosis. Factors that regulate macrophage survival under these conditions are poorly understood. In this study, we identified B cell adapter protein (BCAP), a p85 PI3K-binding adapter protein, in promoting survival in response to the combined challenge of LPS and ER stress. BCAP was unique among nine PI3K adapter proteins in being induced >10-fold in response to LPS. LPS-stimulated macrophages incubated with thapsigargin, a sarcoplasmic/endoplasmic reticulum calcium ATPase inhibitor that induces ER stress, underwent caspase-3 activation and apoptosis. Macrophages from BCAP−/− mice exhibited increased apoptosis in response to these stimuli. BCAP-deficient macrophages demonstrated decreased activation of Akt, but not ERK, and, unlike BCAP-deficient B cells, expressed normal amounts of the NF-κB subunits, c-Rel and RelA. Retroviral transduction of BCAP-deficient macrophages with wild-type BCAP, but not a Y4F BCAP mutant defective in binding the SH2 domain of p85 PI3K, reversed the proapoptotic phenotype observed in BCAP-deficient macrophages. We conclude that BCAP is a nonredundant PI3K adapter protein in macrophages that is required for maximal cell survival in response to ER stress. We suggest that as macrophages engage their pathogenic targets, innate immune receptors trigger increased expression of BCAP, which endows them with the capacity to withstand further challenges from ongoing cellular insults, such as ER stress.

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Section: Bcap Is Required For Maximal Activation Of Akt In Response Tsupporting

confidence: 50%

A Requirement for the p85 PI3K Adapter Protein BCAP in the Protection of Macrophages from Apoptosis Induced by Endoplasmic Reticulum Stress

Song

Chew

Dale

et al. 2011

The Journal of Immunology

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“…First, exposure to hyperoxia induces an altered expression of many of Bcl-2 family members, including both proapoptotic (Bax, Bad, Bak) and antiapoptotic (Bcl-k L, Bclw, Bfl-1 and Bcl-2). These alterations may ultimately lead to an imbalance between pro-and anti-apoptotic Bcl-2 family proteins resulting in cell death [58,59]. In cultured macrophages, hyperoxia can suppress the pro-apoptotic BH3-only protein BimEL in an ERK-dependent manner [59].…”

Section: Expression Of Regulatory Genes In Hyperoxic Cell Deathmentioning

confidence: 99%

“…These alterations may ultimately lead to an imbalance between pro-and anti-apoptotic Bcl-2 family proteins resulting in cell death [58,59]. In cultured macrophages, hyperoxia can suppress the pro-apoptotic BH3-only protein BimEL in an ERK-dependent manner [59]. In addition, over-expression of IL-6 and IL-11 can protect lung cells against hyperoxic cell death in both cell culture and animal models [60,61].…”

Section: Expression Of Regulatory Genes In Hyperoxic Cell Deathmentioning

confidence: 99%

Hyperoxia-induced signal transduction pathways in pulmonary epithelial cells☆

Zaher

Miller

Morrow

et al. 2007

Free Radical Biology and Medicine

121

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Mechanical ventilation with hyperoxia is necessary to treat critically ill patients. However, prolonged exposure to hyperoxia leads to the generation of excessive reactive oxygen species (ROS), which can cause acute inflammatory lung injury. One of the major effects of hyperoxia is the injury and death of pulmonary epithelium, which is accompanied by increased levels of pulmonary proinflammatory cytokines and excessive leukocyte infiltration. A thorough understanding of the signaling pathways leading to pulmonary epithelial cell injury/death may provide some insights into the pathogenesis of hyperoxia-induced acute inflammatory lung injury. This review focuses on epithelial responses to hyperoxia and some of the major factors regulating pathways to epithelial cell injury/death, and proinflammatory responses upon exposure to hyperoxia. We discuss in detail some of the most interesting players, such as, NF-κB, that can modulate both proinflammatory responses and cell injury/death of lung epithelial cells. A better appreciation for the functions of these factors will no doubt help us to delineate the pathways to hyperoxic cell death and proinflammatory responses.

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“…The role of hyperoxia as a potential cause of lung cell injury has been extensively characterized in alveolar epithelial [12][13][14][15][16][17] and endothelial cells [18,19]. However, only a few studies have examined it's impact on alveolar macrophages [20][21][22][23]. Alveolar macrophages provide the first line of defense against inhaled bacterial pathogens [24] and are exposed to 13% oxygen under normal physiological conditions [22].…”

Section: Introductionmentioning

confidence: 99%

“…However, only a few studies have examined it's impact on alveolar macrophages [20][21][22][23]. Alveolar macrophages provide the first line of defense against inhaled bacterial pathogens [24] and are exposed to 13% oxygen under normal physiological conditions [22]. Under conditions of supplemental oxygen therapy, alveolar macrophages, can be exposed to ≥ 95% oxygen.…”

Section: Introductionmentioning

confidence: 99%

Antioxidants preserve macrophage phagocytosis of Pseudomonas aeruginosa during hyperoxia

Morrow

Entezari-Zaher

Romashko

et al. 2007

Free Radical Biology and Medicine

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Pseudomonas. aeruginosa (PA) is a leading cause of nosocomial pneumonia in patients receiving mechanical ventilation with hyperoxia. Exposure to supraphysiological concentrations of reactive oxygen species during hyperoxia may result in macrophage damage that reduces their ability to phagocytose PA. We tested this hypothesis in cultured macrophage-like RAW 264.7 cells and alveolar macrophages from mice exposed to hyperoxia. Exposure to hyperoxia induced a similarly impaired phagocytosis of both the mucoid and non-mucoid forms of PA in alveolar macrophages and RAW cells. Compromised PA phagocytosis was associated with cytoskeleton disorganization and actin oxidation in hyperoxic macrophages. To test whether moderate concentrations of O 2 limit the loss of phagocytic function induced by ≥ 95% O 2 , mice and RAW cells were exposed to 65% O 2 . Interestingly, although the resulting lung injury/cell proliferation was not significant, exposure to 65% O 2 resulted in a marked reduction in PA phagocytosis that was comparable to that of ≥95% O 2 . Treatment with antioxidants, even post hyperoxic exposure, preserved actin cytoskeleton organization and phagocytosis of PA. These data suggest that hyperoxia reduces macrophage phagocytosis through effects on actin functions which can be preserved by antioxidant treatment. In addition, administration of moderate rather than higher concentrations of O 2 does not improve macrophage phagocytosis of PA.

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Macrophages Survive Hyperoxia via Prolonged ERK Activation Due to Phosphatase Down-regulation

Cited by 31 publications

References 53 publications

A Requirement for the p85 PI3K Adapter Protein BCAP in the Protection of Macrophages from Apoptosis Induced by Endoplasmic Reticulum Stress

A Requirement for the p85 PI3K Adapter Protein BCAP in the Protection of Macrophages from Apoptosis Induced by Endoplasmic Reticulum Stress

Hyperoxia-induced signal transduction pathways in pulmonary epithelial cells☆

Antioxidants preserve macrophage phagocytosis of Pseudomonas aeruginosa during hyperoxia

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