FOXO3 Deficiency Leads to Increased Susceptibility to Cigarette Smoke-Induced Inflammation, Airspace Enlargement, and Chronic Obstructive Pulmonary Disease

Hwang, Jae-Woong; Saravanan, R.; Yao, Hongwei; Chung, Sangwoon; Sundar, Isaac K.; Huyck, Heidie; Pryhuber, Gloria S.; Kinnula, Vuokko L.; Rahman, Irfan

doi:10.4049/jimmunol.1001861

Cited by 136 publications

(141 citation statements)

References 66 publications

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“…So far, the role of FOXO in innate immunity is incompletely understood, with literature reporting inflammatory (15,25) and anti-inflammatory effects (42). This juxtaposition is not necessarily a paradox, as it is comparable to former findings regarding FOXO in the context of oxidative cell damage, in which it has been reported that FOXO is able to promote apoptosis as well as cell survival.…”

Section: Discussionsupporting

confidence: 70%

“…Analyzing samples from patients suffering from COPD, cystic fibrosis, and pneumonia/ARDS, we found that FOXO is active during acute and chronic lung infection, which confirms our in vitro data. In contrast to our observations, a recent study by Hwang et al (42) reported that total FOXO is decreased in the lungs of patients with COPD. This discrepancy may be due to differences in patient recruitment or state of disease.…”

Section: Discussioncontrasting

confidence: 55%

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FOXO Transcription Factors Regulate Innate Immune Mechanisms in Respiratory Epithelial Cells

Seiler

Hellberg

Lepper

et al. 2013

The Journal of Immunology

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Bacterial pathogens are a leading cause of lung infections and contribute to acute exacerbations in patients with chronic respiratory diseases. The innate immune system of the respiratory tract controls and prevents colonization of the lung with bacterial pathogens. Forkhead box transcription factor family O (FOXO) transcription factors are key regulators of cellular metabolism, proliferation, and stress resistance. In this study, our aim was to investigate the role of FOXO transcription factors in innate immune functions of respiratory epithelial cells. We show that bacterial pathogens potently activate FOXO transcription factors in cultured human respiratory epithelial cells in vitro. Infection of mice with bacterial pathogens resulted in the activation of FOXO transcription factors in alveolar and bronchial epithelial cells in vivo. Active FOXO was also detectable in human bronchial tissue obtained from subjects with different infection-related lung diseases. Small interfering RNA–mediated knockdown of FOXO in bronchial epithelial cells resulted in reduced expression of factors of the innate immune system such as antimicrobial peptides and proinflammatory cytokines, both under basal conditions and upon infection. FOXO deficiency further affected internalization of Haemophilus influenzae in bronchial epithelial cells. Finally, we show that TLR3 activates innate immune responses in a FOXO-dependent manner. In conclusion, FOXO transcription factors are involved in the cellular responses to bacterial stimuli and act as central regulators of innate immune functions in respiratory epithelial cells.

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Section: Discussionsupporting

confidence: 70%

Section: Discussioncontrasting

confidence: 55%

FOXO Transcription Factors Regulate Innate Immune Mechanisms in Respiratory Epithelial Cells

Seiler

Hellberg

Lepper

et al. 2013

The Journal of Immunology

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“…Since NF-κB is frequently altered in many types of cancers and NF-κB transcriptionally activates c-Myc gene expression, this finding suggests that p27 is reciprocally regulated by FoxO3a and c-Myc. A recent study further suggests that FoxO3a inhibits NF-κB function and that the alteration of FoxO3a is associated with hyper-proliferative helper T cells, cigarette smoke-induced inflammation, airspace enlargement and chronic obstructive pulmonary disease [56,57] . Likewise, FoxO3a also increases several target genes, such as Bim, TRAIL, PUMA and Fas ligand, which all promote cell apoptosis.…”

Section: Foxo3a Functionmentioning

confidence: 99%

“…Clearly, more studies are required to elucidate FoxO3a's function as an effective and useful target capable of preventing or limiting the progression of diseases without clinical compromise. [48] TRAIL Bcr/Abl transformed cells [57] TRAIL Chronic myeloid leukemia [46] PUMA Lymphoid cells [58] Noxa Neuroblastoma [59] FasL Glomerular mesangial cells [102] p27, Caveolin-1 Glomerular mesangial cells [102] p21 Glomerular mesangial cells [102] Shown are previously known FoxO3a target genes that regulate cell proliferation and apoptosis in different cell types. …”

Section: Future Application Of Foxo3amentioning

confidence: 99%

FoxO3a and disease progression

Nho

Hergert

2014

WJBC

140

108

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highlighted as a critical protein that regulates numerous cell functions from proliferation/apoptosis to stressresistance and aging. FoxO3a has been found to be deregulated in several diseases and FoxO3a targeting approaches are currently underway to treat various types of cancers. This review will describe the current concept of FoxO3a's pathological role in various diseases and elucidate the regulatory mechanisms involved. It will also provide the clinical significance and strategies to target FoxO3a to limit the progression of human diseases. INTRODUCTIONForkhead box O (FoxO) transcription factors are the human homologues of the C. elegans transcription factor DAF-16 and share a highly conserved 110-amino acid DNA binding domain, forkhead box or winged-helix domain [1,2] . Forkhead box proteins comprise more than 100 members in humans, classified from FOXA to FOXR [3][4][5] . Members of class O share the characteristic of being regulated by the insulin/PI3K/Akt signaling pathway [4] . Four principal members of the mammalian FoxO subfamily, FoxO1, FoxO3a, FoxO4 and FoxO6 have been previously described [3] . Although they seem to bind a common set of DNA sites, FoxO6 is mainly specific to neurons, while the other 3 FoxO family members are expressed in most tissues. These FoxO members are linked to cell survival, cellular proliferation and DNA damage repair response [5,6] . Among them, FoxO3a has recently been studied extensively as a crucial protein that is involved in the regulation of several essential cellular functions (see page 349). Prior studies have shown that FoxO3a functions as a tumor suppressor by regulating expression of genes in- AbstractThe Forkhead box O (FoxO) family has recently been highlighted as an important transcriptional regulator of crucial proteins associated with the many diverse functions of cells. So far, FoxO1, FoxO3a, FoxO4 and FoxO6 proteins have been identified in humans. Although each FoxO family member has its own role, unlike the other FoxO families, FoxO3a has been extensively studied because of its rather unique and pivotal regulation of cell proliferation, apoptosis, metabolism, stress management and longevity. FoxO3a alteration is closely linked to the progression of several types of cancers, fibrosis and other types of diseases. In this review, we will examine the function of FoxO3a in disease progression and also explore FoxO3a's regulatory mechanisms. We will also discuss FoxO3a as a potential target for the treatment of several types of disease.

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“…The inflammatory cell surface receptor CX3CR1 is upregulated by cigarette smoke exposure; expression of CX3CR1 results in the recruitment of other CX3CR1 positive cells, mainly macrophages and T lymphocytes, amplifying the inflammatory response to cigarette smoke exposure (McComb et al, 2008). Other pathways implicated in modulation of the inflammatory response in smoke exposure include protein phosphatase 2A (PP2A) (Wallace et al, 2012), forkhead box class O 3a (FOXO3) (Hwang et al, 2011), CCR6 , and endothelial monocyte-activating protein 2 (EMAPII) (Clauss et al, 2011).…”

Section: Lessons From Chronic and Acute Smoke Exposure Studiesmentioning

confidence: 99%

Second hand smoke and COPD: lessons from animal studies

2015

Frontiers Research Topics

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Exposure to second hand smoke is a major cause of chronic obstructive pulmonary disease (COPD) in the non-smoker. In this review we explore the use of animal smoke exposure models and their insight into disease pathogenesis. The methods of smoke exposure, including exposure delivery systems, are described. Key findings from the acute and chronic smoke exposure models are outlined, including descriptions of the inflammation processes, proteases involved, oxidative stress, and apoptosis. Finally, alternatives to rodent models of lung disease are presented.

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FOXO3 Deficiency Leads to Increased Susceptibility to Cigarette Smoke-Induced Inflammation, Airspace Enlargement, and Chronic Obstructive Pulmonary Disease

Cited by 136 publications

References 66 publications

FOXO Transcription Factors Regulate Innate Immune Mechanisms in Respiratory Epithelial Cells

FOXO Transcription Factors Regulate Innate Immune Mechanisms in Respiratory Epithelial Cells

FoxO3a and disease progression

Second hand smoke and COPD: lessons from animal studies

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