T<sub>H</sub>17 Cells in Asthma and COPD

Alcorn, John F.; Crowe, Christopher R.; Kolls, Jay K.

doi:10.1146/annurev-physiol-021909-135926

Cited by 315 publications

(260 citation statements)

References 182 publications

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“…Noneosinophilic asthma associated with neutrophilic inflammation is generally refractive to treatment with steroids 42,43). Multiple mechanisms have been identified by which Th17 cells can cause steroid-resistant asthma (44). It is recognized that IL-17 family members induce granulopoiesis, neutrophil chemotaxis, and the antiapoptotic properties of G-CSF (45,46).…”

Section: Discussionmentioning

confidence: 99%

Trithorax complex component Menin controls differentiation and maintenance of T helper 17 cells

Watanabe¹,

Onodera²,

Kanai³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Epigenetic modifications, such as posttranslational modifications of histones, play an important role in gene expression and regulation. These modifications are in part mediated by the Trithorax group (TrxG) complex and the Polycomb group (PcG) complex, which activate and repress transcription, respectively. We herein investigate the role of Menin, a component of the TrxG complex in T helper (Th) cell differentiation and show a critical role for Menin in differentiation and maintenance of Th17 cells. Menin −/− T cells do not efficiently differentiate into Th17 cells, leaving Th1 and Th2 cell differentiation intact in in vitro cultures. Menin deficiency resulted in the attenuation of Th17-induced airway inflammation. In differentiating Th17 cells, Menin directly bound to the Il17a gene locus and was required for the deposition of permissive histone modifications and recruitment of the RNA polymerase II transcriptional complex. Interestingly, although Menin bound to the Rorc locus, Menin was dispensable for the induction of Rorc expression and permissive histone modifications in differentiating Th17 cells. In contrast, Menin was required to maintain expression of Rorc in differentiated Th17 cells, indicating that Menin is essential to stabilize expression of the Rorc gene. Thus, Menin orchestrates Th17 cell differentiation and function by regulating both the induction and maintenance of target gene expression.

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Section: Discussionmentioning

confidence: 99%

Trithorax complex component Menin controls differentiation and maintenance of T helper 17 cells

Watanabe¹,

Onodera²,

Kanai³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…IL-17 has been linked to a number of autoimmune and allergic diseases (44)(45)(46). Clinical data have associated Th17 cells, IL-17, and increased neutrophilia with severe asthma.…”

Section: Discussionmentioning

confidence: 99%

Dose-Dependent Effects of IL-17 on IL-13–Induced Airway Inflammatory Responses and Airway Hyperresponsiveness

Kinyanjui

Shan

Nakada

et al. 2013

The Journal of Immunology

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The Th2 cytokine IL-13 regulates several aspects of the asthmatic phenotype, including airway inflammation, airway hyperresponsiveness, and mucus production. The Th17 cytokine IL-17A is also implicated in asthma and has been shown to both positively and negatively regulate Th2-dependent responses in murine models of allergic airways disease. Our objective in this study was to better understand the role of IL-17 in airway inflammation by examining how IL-17 modifies IL-13–induced airway inflammatory responses. We treated BALB/c mice intranasally with IL-13 or IL-17 alone or in combination for 8 consecutive days, after which airway hyperresponsiveness, inflammatory cell influx into the lung, and lung chemokine/cytokine expression were assessed. As expected, IL-13 increased airway inflammation and airway hyperresponsiveness. IL-13 also increased numbers of IL-17–producing CD4+ and γδ T cells. Treating mice with a combination of IL-13 and IL-17 reduced infiltration of IL-17+ γδ T cells, but increased the number of infiltrating eosinophils. In contrast, coadministration of IL-13 with a higher dose of IL-17 decreased all IL-13–induced inflammatory responses, including infiltration of both IL-17+CD4+ and γδ T cells. To examine the inhibitory activity of IL-17–expressing γδ T cells in this model, these cells were adoptively transferred into naive recipients. Consistent with an inhibitory role for γδ T cells, IL-13–induced infiltration of eosinophils, lymphocytes, and IL-17+CD4+ T cells was diminished in recipients of the γδ T cells. Collectively, our data indicate that allergic airway inflammatory responses induced by IL-13 are modulated by both the quantity and the cellular source of IL-17.

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“…Although a significant body of research has focused on understanding the effects of IL-13, IL-17A, and other cytokines on coordinating the immune response in asthma (17,23,(44)(45)(46), the importance of these mediators on ASM contractility has been more recently appreciated (2,4). Most of the therapeutic strategies in asthma target specific steps of the inflammatory response with varying success (47).…”

Section: Discussionmentioning

confidence: 99%

Mfge8 suppresses airway hyperresponsiveness in asthma by regulating smooth muscle contraction

Kudo

Soltani

Sakuma

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Airway obstruction is a hallmark of allergic asthma and is caused primarily by airway smooth muscle (ASM) hypercontractility. Airway inflammation leads to the release of cytokines that enhance ASM contraction by increasing ras homolog gene family, member A (RhoA) activity. The protective mechanisms that prevent or attenuate the increase in RhoA activity have not been well studied. Here, we report that mice lacking the gene that encodes the protein Milk Fat Globule-EGF factor 8 (Mfge8 −/− ) develop exaggerated airway hyperresponsiveness in experimental models of asthma. Mfge8 −/− ASM had enhanced contraction after treatment with IL-13, IL-17A, or TNF-α. Recombinant Mfge8 reduced contraction in murine and human ASM treated with IL-13. Mfge8 inhibited IL-13-induced NF-κB activation and induction of RhoA. Mfge8 also inhibited rapid activation of RhoA, an effect that was eliminated by an inactivating point mutation in the RGD integrin-binding site in recombinant Mfge8. Human subjects with asthma had decreased Mfge8 expression in airway biopsies compared with healthy controls. These data indicate that Mfge8 binding to integrin receptors on ASM opposes the effect of allergic inflammation on RhoA activity and identify a pathway for specific inhibition of ASM hypercontractility in asthma.calcium sensitivity | lactadherin

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T_H17 Cells in Asthma and COPD

Cited by 315 publications

References 182 publications

Trithorax complex component Menin controls differentiation and maintenance of T helper 17 cells

Trithorax complex component Menin controls differentiation and maintenance of T helper 17 cells

Dose-Dependent Effects of IL-17 on IL-13–Induced Airway Inflammatory Responses and Airway Hyperresponsiveness

Mfge8 suppresses airway hyperresponsiveness in asthma by regulating smooth muscle contraction

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TH17 Cells in Asthma and COPD

Cited by 315 publications

References 182 publications

Trithorax complex component Menin controls differentiation and maintenance of T helper 17 cells

Trithorax complex component Menin controls differentiation and maintenance of T helper 17 cells

Dose-Dependent Effects of IL-17 on IL-13–Induced Airway Inflammatory Responses and Airway Hyperresponsiveness

Mfge8 suppresses airway hyperresponsiveness in asthma by regulating smooth muscle contraction

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T_H17 Cells in Asthma and COPD