Modulation of the Mevalonate Pathway by Akt Regulates Macrophage Survival and Development of Pulmonary Fibrosis

Larson‐Casey, Jennifer L.; Murthy, Shubha; Ryan, Alan J.; Carter, A. Brent

doi:10.1074/jbc.m114.593285

Cited by 31 publications

(41 citation statements)

References 74 publications

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“…Indeed, PKB appears to promote M2 polarization, as inactivation of PKB leads to a defect of IL4-induced M2 polarization in TSC-deficient macrophages [113]. This is further supported by a PKB haplodeficient pulmonary fibrosis model [114]. However, in line with M1 activation signals activating PKB, several studies also demonstrate that PKB indeed is critically involved in promoting M1 macrophage activation [115,116].…”

Section: Pkb Regulated Macrophage Functionmentioning

confidence: 78%

PKB/Akt-dependent regulation of inflammation in cancer

Tang

Wang

Hemmings

et al. 2018

Seminars in Cancer Biology

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A B S T R A C TChronic inflammation is a major cause of human cancer. Clinical cancer therapies against inflammatory risk factors are strategically determined. To rationally guide a novel drug development, an improved mechanistic understanding on the pathological connection between inflammation and carcinogenesis is essential. PI3K-PKB signaling axis has been extensively studied and shown to be one of the key oncogenic drivers in most types of cancer. Pharmacological inhibition of the components along this signaling axis is of great interest for developing novel therapies. Interestingly, emerging studies have shown a close association between PKB activation and inflammatory activity in the vicinity of the tumor, and either blockade of PKB or attenuation of para-tumoral inflammation reveals a mutual-interactive pattern through pathway crosstalk. In this review, we intend to discuss recent advances of PKB-regulated chronic inflammation and its potential impacts on tumor development.

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Section: Pkb Regulated Macrophage Functionmentioning

confidence: 78%

PKB/Akt-dependent regulation of inflammation in cancer

Tang

Wang

Hemmings

et al. 2018

Seminars in Cancer Biology

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“…Because Akt is often altered in human disease and can be activated by many cellular stimuli or toxic insults (Govindarajan et al, 2007; Larson-Casey et al, 2014), we measured the expression of Akt1 in alveolar macrophages from normal subjects and IPF patients. Alveolar macrophages showed a 3-fold increase of p-Akt1 in IPF patients compared to normal subjects (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Protein kinase B, or Akt1, a pro-survival kinase, is known to mediate mitochondrial H 2 O 2 generation (Larson-Casey et al, 2014), and mitochondrial ROS plays an important role in macrophage innate immunity (West et al, 2011). Although mitochondrial ROS is usually considered toxic, it also has beneficial effects, such as modulating mitochondrial dynamics.…”

Section: Introductionmentioning

confidence: 99%

Macrophage Akt1 Kinase-Mediated Mitophagy Modulates Apoptosis Resistance and Pulmonary Fibrosis

et al. 2016

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Summary Idiopathic pulmonary fibrosis (IPF) is a devastating lung disorder with increasing incidence. Mitochondrial oxidative stress in alveolar macrophages is directly linked to pulmonary fibrosis. Mitophagy, the selective engulfment of dysfunctional mitochondria by autophagasomes, is important for cellular homeostasis and can be induced by mitochondrial oxidative stress. Here, we show Akt1 induced macrophage mitochondrial reactive oxygen species (ROS) and mitophagy. Mice harboring a conditional deletion of Akt1 in macrophages (Akt1−/−Lyz2-cre) and Park2−/− mice had impaired mitophagy and reduced active transforming growth factor-β1 (TGF-β1). Although Akt1 increased TGF-β1 expression, mitophagy inhibition in Akt1-overexpressing macrophages abrogated TGF-β1 expression and fibroblast differentiation. Importantly, conditional Akt1−/− Lyz2-cre mice and Park2−/− mice had increased macrophage apoptosis and were protected from pulmonary fibrosis. Moreover, IPF alveolar macrophages had evidence of increased mitophagy and display apoptosis resistance. These observations suggest that Akt1-mediated mitophagy contributes to alveolar macrophage apoptosis resistance and is required for pulmonary fibrosis development.

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“…Because HMG-CoA is a proximal enzyme in the isoprenoid pathway it may alter cell membrane integrity and reduce the N -glycosylation of growth-factor receptors. Statins also activate Akt (31), and multiple studies show that Akt is linked to fibrosis development (32-37). Moreover, statins are potent anti-inflammatory agents (38-40), so it is plausible that statins have a role in the polarization of macrophages to an M2 phenotype, which are anti-inflammatory and repair injured tissue (41-43); however, an imbalance of macrophages with a predominance of an M2 phenotype can promote fibrosis (19,44).…”

Section: Discussionmentioning

confidence: 99%

Targeting the isoprenoid pathway to abrogate progression of pulmonary fibrosis

Osborn-Heaford

Murthy

et al. 2015

Free Radical Biology and Medicine

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Fibrotic remodeling in lung injury is a major cause of morbidity. The mechanism that mediates the ongoing fibrosis is unclear, and there is no available treatment to abate the aberrant repair. Reactive oxygen species (ROS) have a critical role in inducing fibrosis by modulating extracellular matrix deposition. Specifically, mitochondrial hydrogen peroxide (H2O2) production by alveolar macrophages is directly linked to pulmonary fibrosis as inhibition of mitochondrial H2O2 attenuates the fibrotic response in mice. Prior studies indicate that the small GTP-binding protein, Rac1, directly mediates H2O2 generation in the mitochondrial intermembrane space. Geranylgeranylation of the C-terminal cysteine residue (Cys189) is required for the for Rac1 activation and mitochondrial import. We hypothesized that impairment of geranylgeranylation would limit mitochondrial oxidative stress, and, thus, abrogate progression of pulmonary fibrosis. By targeting the isoprenoid pathway with a novel agent, digeranyl bisphosphonate (DGBP), which impairs geranylgeranylation, we demonstrate that Rac1 mitochondrial import, mitochondrial oxidative stress, and progression of the fibrotic response to lung injury are significantly attenuated. These observations reveal that targeting the isoprenoid pathway to alter Rac1 geranylgeranylation halts the progression of pulmonary fibrosis after lung injury.

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Modulation of the Mevalonate Pathway by Akt Regulates Macrophage Survival and Development of Pulmonary Fibrosis

Cited by 31 publications

References 74 publications

PKB/Akt-dependent regulation of inflammation in cancer

PKB/Akt-dependent regulation of inflammation in cancer

Macrophage Akt1 Kinase-Mediated Mitophagy Modulates Apoptosis Resistance and Pulmonary Fibrosis

Targeting the isoprenoid pathway to abrogate progression of pulmonary fibrosis

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