FOXO Transcription Factors Regulate Innate Immune Mechanisms in Respiratory Epithelial Cells

Abstract

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.

Leishmania donovani inhibits macrophage apoptosis and pro-inflammatory response through AKT-mediated regulation of β-catenin and FOXO-1

“…As β-catenin has a role in modulating FOXO-1 (ref 28), another protein known to regulate both apoptosis and inflammation; [18][19][20] therefore, we studied the status of this protein in infection and found a time dependent increase in phosphorylation of FOXO-1, which corroborated with the kinetics of its cytoplasmic translocation. This confirms that phosphorylation of FOXO-1 at Ser 256 residue results in its nuclear export during infection, as unphosphorylated active FOXO-1 is known to be retained in nucleus.…”

“…Sporadic evidences indicate that β-catenin inhibits inflammation in a GSK-3β-dependent manner whereas FOXO-1 has also been implicated in regulation of pro-inflammatory responses. [18][19][20] By using constitutively active FOXO-1, its importance was shown in regulating the inflammatory responses both in the context of LPS induction or free fatty acid administration. 19 Moreover, administration of siRNA targeting FOXO-1 resulted in decreased inflammatory responses in H. influenzae infection.…”

“…19 Moreover, administration of siRNA targeting FOXO-1 resulted in decreased inflammatory responses in H. influenzae infection. 20 β-catenin limits NF-κB mediated inflammatory responses in both Salmonella infection and TNF-α treatment by stabilizing Iκβ. 21 We, therefore, were interested to determine whether these two downstream effector molecules of AKT are modulated by infection.…”

Disease tolerance and immunity in host protection against infection

“…FOXO activation orchestrates a metabolic response that allows essential cellular functional outputs to be maintained under sub-optimal glucose supply 151 . FOXO activation in epithelial cells regulates the expression of anti-oxidant 152 and antimicrobial genes 153 that contribute to maintain epithelial barrier integrity, acting in a protective manner against infection in flies 152, 153 and mice 153,154 . However, activation of FOXO1 and FOXO3α in muscle cells, promotes myofiber atrophy and muscle wasting associated with sepsis in mice 155 and Mycobacterium marinum infection in flies 127 .…”

Hypoxia and the hypoxia-regulated transcription factor HIF-1α suppress the host defence of airway epithelial cells

“…32,33 Calu-3 cells were cultured in DMEM/F12 (Life Technologies, Darmstadt, Germany) supplemented with 10% FCS, 100 IU/ml penicillin G and 100 IU/ml streptomycin sulfate. Prior to cell-culture experiments, Calu-3 cells were serum-starved overnight and experiments were carried out in serum-free DMEM/F12.…”