Transcription factor Foxo1 is essential for IL-9 induction in T helper cells

Malik, Sakshi; Sadhu, Srikanth; Elesela, Srikanth; Pandey, Ramendra Pati; Chawla, Amanpreet Singh; Sharma, Deepak; Panda, Lipsa; Rathore, Deepak Kumar; Ghosh, Balram; Ahuja, Vineet; Awasthi, Amit

doi:10.1038/s41467-017-00674-6

Cited by 93 publications

(106 citation statements)

References 63 publications

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“…Pro‐asthmatic M2 macrophage phenotypes are mainly arbitrated through specific IRF4 transcription factor pathway; therefore, FoxO1 could regulate a key checkpoint of the IRF4 pathway in macrophages. Our data are consistent with this literature that FoxO1 regulates the macrophage inflammatory phenotype through an IRF4‐dependent manner in allergic inflammation and in asthma biology . Mechanistically, FoxO1 is known to bind to IRF4 promoter and mediate transactivation .…”

Section: Discussionsupporting

confidence: 93%

“…Limitation to the current study includes the relatively small number of human samples; however, our results are consistent with the expression of FoxO1 in macrophages that is required for the pro‐asthmatic phenotype which contributes to aggravating the inflammatory reaction of DRA‐induced allergic asthma. Very recent reports have also demonstrated a crucial role of FoxO1 in other type of asthmatic inflammation . Our data, in combination with the literature, suggest that the impact of FoxO1 on the macrophage inflammatory phenotype is transduced through expression of the binding partner, IRF4.…”

Section: Discussionsupporting

confidence: 82%

“…Interestingly, FoxO1 possess bifunctional role in anti‐ and pro‐inflammatory properties depending on context and binding partners . Recent literature has reported that the expression of FoxO1 enhances the development of Th9 cells in allergic inflammation . Notably, IL‐9 was shown to be associated with Th2 cells in allergic inflammation models .…”

Section: Discussionmentioning

confidence: 99%

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FoxO1 is a critical regulator of M2‐like macrophage activation in allergic asthma

Chung

Kim

Song

et al. 2018

Allergy

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Background: The pathogenesis of asthma and airway obstruction is the result of an abnormal response to different environmental exposures. The scientific premise of our study was based on the finding that FoxO1 expression is increased in lung macrophages of mice after allergen exposure and human asthmatic patients. Macrophages are capable of switching from one functional phenotype to another, and it is important to understand the mechanisms involved in the transformation of macrophages and how their cellular function affects the peribronchial stromal microenvironment. Methods:We employed a murine asthma model, in which mice were treated by intranasal insufflation with allergens for 2-8 weeks. We used both a pharmacologic approach using a highly specific FoxO1 inhibitor and genetic approaches using FoxO1 knockout mice (FoxO1 fl/fl LysMcre). Cytokine level in biological fluids was measured by ELISA and the expression of encoding molecules by NanoString assay and qRT-PCR.Results: We show that the levels of FoxO1 gene are significantly elevated in the airway macrophages of patients with mild asthma in response to subsegmental bronchial allergen challenge. Transcription factor FoxO1 regulates a pro-asthmatic phenotype of lung macrophages that is involved in the development and progression of chronic allergic airway disease. We have shown that inhibition of FoxO1 induced phenotypic conversion of lung macrophages and downregulates pro-asthmatic and pro-fibrotic gene expression by macrophages, which contribute to airway inflammation and airway remodeling in allergic asthma.Conclusion: Targeting FoxO1 with its downstream regulator IRF4 is a novel therapeutic target for controlling allergic inflammation and potentially reversing fibrotic airway remodeling.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

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FoxO1 is a critical regulator of M2‐like macrophage activation in allergic asthma

Chung

Kim

Song

et al. 2018

Allergy

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“…Other transcriptional activators, which have been described to bind to the IL9 promoter and were found to be overexpressed with age, include HIF1α, GATA3, and ETV5 (Kaplan, ; Malik et al, ; Singh, Garden, Lang, & Cobb, ; Wang et al, ). In contrast, BCL6 and ID3, transcriptional repressors of IL9, declined with age.…”

Section: Discussionmentioning

confidence: 99%

Transcription factor networks in aged naïve CD4 T cells bias lineage differentiation

Li²,

Ye³

et al. 2019

Aging Cell

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With reduced thymic activity, the population of naïve T cells in humans is maintained by homeostatic proliferation throughout adult life. In young adults, naïve CD4 T cells have enormous proliferative potential and plasticity to differentiate into different lineages. Here, we explored whether naïve CD4 T‐cell aging is associated with a partial loss of this unbiased multipotency. We find that naïve CD4 T cells from older individuals have developed a propensity to develop into TH9 cells. Two major mechanisms contribute to this predisposition. First, responsiveness to transforming growth factor β (TGFβ) stimulation is enhanced with age due to an upregulation of the TGFβR3 receptor that results in increased expression of the transcription factor PU.1. Secondly, aged naïve CD4 T cells display altered transcription factor profiles in response to T‐cell receptor stimulation, including enhanced expression of BATF and IRF4 and reduced expression of ID3 and BCL6. These transcription factors are involved in TH9 differentiation as well as IL9 transcription suggesting that the aging‐associated changes in the transcription factor profile favor TH9 commitment.

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“…31,47 IL-5 and IL-9 were recognized to be Th2-associated cytokines and involved in inflammation regulation. 48,49 It was worth noting that the expression of IL-4 in NT-30 is lower than that of P and NT-100 at 3 days. In another study conducted by our group, we found that there were more mast cell infiltrations around the P and NT-100 groups within 3 days after implantation (data not shown).…”

mentioning

confidence: 99%

Nanostructured titanium regulates osseointegration via influencing macrophage polarization in the osteogenic environment

Wang¹,

Meng²,

Song³

et al. 2018

IJN

101

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IntroductionFabricating nanostructured surface topography represents the mainstream approach to induce osteogenesis for the next-generation bone implant. In the past, the bone implant was designed to minimize host repulsive reactions in order to acquire biocompatibility. However, increasing reports indicate that the absence of an appropriate immune response cannot acquire adequate osseointegration after implantation in vivo.Materials and methodsWe prepared different topographies on the surface of titanium (Ti) specimens by grinding, etching and anodizing, and they were marked as polished specimen (P), specimen with nanotubes (NTs) in small diameters (NT-30) and specimen with NTs in large diameters (NT-100). We evaluated the ability of different topographies of the specimen to induce osteogenic differentiation of mice bone marrow mesenchymal stem cells (BMSCs) in vitro and to induce osseointegration in vivo. Furthermore, we investigated the effect of different topographies on the polarization and secretion of macrophages, and the effect of macrophage polarization on topography-induced osteogenic differentiation of mice BMSCs. Finally, we verified the effect of macrophage polarization on topography-induced osseointegration in vivo by using Cre*RBP-Jfl/fl mice in which classically activated macrophage was restrained.ResultsThe osteogenic differentiation of mice BMSCs induced by specimen with different topographies was NT-100>NT-30>P, while the osseointegration induced by specimen with different topographies in vivo was NT-30>NT-100>P. In addition, specimen of NT-30 could induce more macrophages to M2 polarization, while specimen of P and NT-100 could induce more macrophages to M1 polarization. When co-culture mice BMSCs and macrophages on specimen with different topographies, the osteogenic differentiation of mice BMSCs was NT-30>NT-100≥P. The osseointegration induced by NT-100 in Cre*RBP-Jfl/fl mice was much better than that of wild type mice.ConclusionIt is suggested that the intrinsic immunomodulatory effects of nanomaterials are not only crucial to evaluate the in vivo biocompatibility but also required to determine the final osseointegration. To clarify the immune response and osseointegration may be beneficial for the designation and optimization of the bone implant.

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Transcription factor Foxo1 is essential for IL-9 induction in T helper cells

Cited by 93 publications

References 63 publications

FoxO1 is a critical regulator of M2‐like macrophage activation in allergic asthma

FoxO1 is a critical regulator of M2‐like macrophage activation in allergic asthma

Transcription factor networks in aged naïve CD4 T cells bias lineage differentiation

Nanostructured titanium regulates osseointegration via influencing macrophage polarization in the osteogenic environment

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