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.

18 Reads
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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.
    British Journal of Pharmacology 01/2015; 172(10). DOI:10.1111/bph.13080 · 4.84 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: High mobility group box chromosomal protein 1 (HMGB1) is a critical pro-inflammatory cytokine involved in diverse inflammatory diseases and has important immunomodulatory effects on allergic asthma. Our recent studies demonstrate that HMGB1) ^ReloadFigure=Yes1 expression increases in the lung tissue and associates with interleukin-17+ (IL-17) helper T cell (Th17) responses in a murine model of neutrophilic asthma. In this study, to examine the immunomodulatory mechanisms of HMGB1, we evaluated the effects of recombinant HMGB1 A box (an antagonist of HMGB1) administration on allergic airway inflammation and lung antigen-presenting cell (APC) function in a murine model of neutrophilic asthma. In OVA-challenged mice, rHMGB1 A box attenuated HMGB1 expression, airway neutrophilic inflammation and hyper-responsiveness. In addition, the administration of rHMGB1 A box decreased the number of Th17 cells and IL-23+ CD11c+ APCs in lung cells. In vivo, rHMGB1 A box revealed an inhibitory effect of rHMGB1-activated dendritic cells (DCs) to produce IL-23 and induce a Th17 response. Finally, we showed that adoptive transfer of rHMGB1-activated DCs was sufficient to restore the characteristics of neutrophilic asthma in a DCs-driven model of asthma, whereas the transfer of rHMGB1 A box plus rHMGB1-activated DCs significantly reduced these inflammation phenotypes. These data demonstrate that rHMGB1 A box may have therapeutic effects on controlling Th17 polarization and airway inflammation in neutrophilic asthma by blocking the HMGB1 pathway on DCs.
    International Immunopharmacology 11/2014; 24(1). DOI:10.1016/j.intimp.2014.11.005 · 2.47 Impact Factor
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: IL-22 is a Th17/Th22 cytokine that is increased in asthma. However, recent animal studies showed controversial findings in the effects of IL-22 in allergic asthma. To determine the role of IL-22 in ovalbumin-induced allergic inflammation we generated inducible lung-specific IL-22 transgenic mice. Transgenic IL-22 expression and signaling activity in the lung were determined. Ovalbumin (OVA)-induced pulmonary inflammation, immune responses, and airway hyperresponsiveness (AHR) were examined and compared between IL-22 transgenic mice and wild type controls. Following doxycycline (Dox) induction, IL-22 protein was readily detected in the large (CC10 promoter) and small (SPC promoter) airway epithelial cells. IL-22 signaling was evidenced by phosphorylated STAT3. After OVA sensitization and challenge, compared to wild type littermates, IL-22 transgenic mice showed decreased eosinophils in the bronchoalveolar lavage (BAL), and in lung tissue, decreased mucus metaplasia in the airways, and reduced AHR. Among the cytokines and chemokines examined, IL-13 levels were reduced in the BAL fluid as well as in lymphocytes from local draining lymph nodes of IL-22 transgenic mice. No effect was seen on the levels of serum total or OVA-specific IgE or IgG. These findings indicate that IL-22 has immune modulatory effects on pulmonary inflammatory responses in allergen-induced asthma.
    PLoS ONE 09/2014; 9(9):e107454. DOI:10.1371/journal.pone.0107454 · 3.23 Impact Factor
Show more


18 Reads
Available from