TH17 Cells Mediate Steroid-Resistant Airway Inflammation and Airway Hyperresponsiveness in Mice

Department of Pediatrics, Lung Immunology and Host Defense Laboratory, University of Pittsburgh, Pittsburgh, PA 15213, USA.
The Journal of Immunology (Impact Factor: 4.92). 10/2008; 181(6):4089-97. DOI: 10.1542/peds.2009-1870DDD
Source: PubMed


Steroid-resistant asthma comprises an important source of morbidity in patient populations. T(H)17 cells represent a distinct population of CD4(+) Th cells that mediate neutrophilic inflammation and are characterized by the production of IL-17, IL-22, and IL-6. To investigate the function of T(H)17 cells in the context of Ag-induced airway inflammation, we polarized naive CD4(+) T cells from DO11.10 OVA-specific TCR-transgenic mice to a T(H)2 or T(H)17 phenotype by culturing in conditioned medium. In addition, we also tested the steroid responsiveness of T(H)2 and T(H)17 cells. In vitro, T(H)17 cytokine responses were not sensitive to dexamethasone (DEX) treatment despite immunocytochemistry confirming glucocorticoid receptor translocation to the nucleus following treatment. Transfer of T(H)2 cells to mice challenged with OVA protein resulted in lymphocyte and eosinophil emigration into the lung that was markedly reduced by DEX treatment, whereas T(H)17 transfer resulted in increased CXC chemokine secretion and neutrophil influx that was not attenuated by DEX. Transfer of T(H)17 or T(H)2 cells was sufficient to induce airway hyperresponsiveness (AHR) to methacholine. Interestingly, AHR was not attenuated by DEX in the T(H)17 group. These data demonstrate that polarized Ag-specific T cells result in specific lung pathologies. Both T(H)2 and T(H)17 cells are able to induce AHR, whereas T(H)17 cell-mediated airway inflammation and AHR are steroid resistant, indicating a potential role for T(H)17 cells in steroid-resistant asthma.

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    • "activity and increase phosphoinositide 3 kinase (PI3K)/Akt pathway activation, all of which can reduce corticosteroid sensitivity (Strickland et al., 2001; Ito et al., 2008; Mercado et al., 2011). Neutrophilia in steroid-insensitive mice is associated with high levels of IL-8 and IL- 17 (McKinley et al., 2008), which are likely to be important in sustaining the raised neutrophilia observed with allergen and LPS co-administration. Indeed, IL-8 levels were raised significantly above naïve levels by Ova and LPS co-administration. "
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    ABSTRACT: Asthma exacerbations contribute to corticosteroid insensitivity. Lipopolysaccharide (LPS) is ubiquitous in the environment. It causes bronchoconstriction and airways inflammation and may therefore exacerbate allergen responses. This study examined whether LPS and ovalbumin co-administration could exacerbate the airways inflammatory and functional responses to ovalbumin in conscious guinea-pigs and whether these exacerbated responses were insensitive to inhaled corticosteroid treatment with fluticasone propionate. Guinea-pigs were sensitized and challenged with ovalbumin and airways function recorded as specific airways conductance (sGaw) by whole body plethysmography. Airways inflammation was measured from lung histology and bronchoalveolar lavage. Airways hyperreactivity (AHR) to inhaled histamine was examined 24h after ovalbumin. LPS was inhaled alone or 24 or 48 hours before ovalbumin and combined with ovalbumin. Fluticasone propionate (0.05, 0.1, 0.5 or 1mg/ml) or vehicle (ethanol:DMSO:saline 30:30:40) was nebulised for 15 minutes twice daily for 6 days before ovalbumin or LPS exposure. Ovalbumin inhalation caused early (EAR) and late asthmatic responses (LAR), airways hypereactivity to histamine and influx of inflammatory cells into the lungs. LPS 48 hours before and co-administered with ovalbumin exacerbated the response with increased length of the EAR, prolonged response to histamine and elevated inflammatory cells. FP 0.5 and 1mg/ml reduced the LAR, AHR and cell influx with ovalbumin alone, but was ineffective when guinea-pigs were exposed to LPS before and with ovalbumin. LPS exposure exacerbates airways inflammatory and functional responses to allergen inhalation and decreases corticosteroid sensitivity. Its widespread presence in the environment could contribute to asthma exacerbations and corticosteroid insensitivity in humans. This article is protected by copyright. All rights reserved.
    Full-text · Article · Jan 2015 · British Journal of Pharmacology
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    • "Th17 cells are a distinct subset of T cells that have been found to produce interleukin 17 (IL-17), and play an important role in the development of non-eosinophilic asthma (NEA), resulting in more severe phenotypes and steroid-resistant neutrophilic airway inflammation [4] [5] [6]. For example, passive Th17 transfer in mice induces neutrophilic airway inflammation and airway hyper-responsiveness (AHR), which are not attenuated by steroids, indicating a potential role for Th17 cells in steroid-resistant asthma [7]; IL-17 is a pro-inflammatory cytokine mainly secreted from helper T (Th) 17 cells, and it is important for the induction of neutrophil recruitment and migration at sites of inflammation [8]; Th17-related cytokines in sputum are significantly elevated in severe asthmatics and are correlated with sputum neutrophil counts [9]. The evidence suggests that Th17 cells are important in promoting and sustaining neutrophilic inflammation as observed in severe asthma. "
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    Full-text · Article · Nov 2014 · International Immunopharmacology
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    • "Th2 cytokines, IL-4 and IL-13, play a central role in orchestrating these responses, whereas Th1 cytokine IFN-γ may have opposing effects [1]–[4]. Furthermore, the Th17 cytokine IL-17A is critical in the pathogenesis of severe asthma [4], [5]. Recently, a novel Th17/Th22 cytokine, IL-22, was found to have immune modulatory effects on pulmonary allergic inflammation [6]–[8]. "
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    Full-text · Article · Sep 2014 · PLoS ONE
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