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      Lipopolysaccharide Exposure Alleviates Asthma in Mice by Regulating Th1/Th2 and Treg/Th17 Balance

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          Abstract

          Background

          It is generally believed that endotoxin exposure exacerbates risk of developing asthmatic symptoms. However, recent studies have indicated that prior bacterial exposure may prevent future symptoms of asthma. Here, we evaluated the influence of pre-exposure to different concentrations of lipopolysaccharide (LPS) to subsequent ovalbumin (OVA) allergen sensitization and challenge.

          Material/Methods

          Four-week-old Balb/c mice were treated intranasally with varying concentrations of LPS (1 ug, 10 ug, and 100 ug) or sterile PBS for 10 days, then 2 weeks later they were exposed to OVA. Both the molecular and functional airway responses to OVA administration were assessed following prior exposure to different doses of LPS or controls. Additionally, the Th1/Th2 and Treg/Th17 balance was measured.

          Results

          Airway responsiveness and immune cell recruitment in the bronchoalveolar lavage (BALF) were decreased in animals exposed to a low dose of LPS (1 ug) treatment compared with the asthma group. Moderate-dose (10 ug) and high-dose (100 ug) LPS administration showed no differences from controls. Further, low-dose LPS (1 ug) exposure was associated with increased Th1 cytokines, T-bet, Treg cytokine (IL-10, TGF-β), and Foxp3 expression, but decreased Th2 cytokines (IL-4,5,13), GATA3, Th17, and ROR-γt expression compared with the asthma group. Finally, higher numbers of CD4+CD25+Foxp3+Treg cells, and CD4+INF-γ+T cells, and lower CD4+IL-4+T cells and CD4+IL-17+T cells were observed in the low-dose LPS-treated groups compared to controls.

          Conclusions

          Our findings suggest that prior exposure to low doses of LPS may protect from OVA-induced airway hyperresponsiveness (AHR) and histopathologic changes through regulation of the Th1/Th2 and Treg/Th17 balance.

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          Most cited references41

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          Requirement for IL-13 independently of IL-4 in experimental asthma.

          The pathogenesis of asthma reflects, in part, the activity of T cell cytokines. Murine models support participation of interleukin-4 (IL-4) and the IL-4 receptor in asthma. Selective neutralization of IL-13, a cytokine related to IL-4 that also binds to the alpha chain of the IL-4 receptor, ameliorated the asthma phenotype, including airway hyperresponsiveness, eosinophil recruitment, and mucus overproduction. Administration of either IL-13 or IL-4 conferred an asthma-like phenotype to nonimmunized T cell-deficient mice by an IL-4 receptor alpha chain-dependent pathway. This pathway may underlie the genetic associations of asthma with both the human 5q31 locus and the IL-4 receptor.
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            B7-1 and B7-2 costimulatory molecules activate differentially the Th1/Th2 developmental pathways: application to autoimmune disease therapy.

            CD4 T helper precursor cells mature along two alternative pathways, Th1 and Th2. Here we show that these pathways are differentially activated by two costimulatory molecules, B7-1 and B7-2. Using anti-B7 antibodies, this developmental step was manipulated both in vitro and in vivo in experimental allergic encephalomyelitis (EAE). Anti-B7-1 reduced the incidence of disease while anti-B7-2 increased disease severity. Neither antibody affected overall T cell induction but rather altered cytokine profile. Administration of anti-B7-1 at immunization resulted in predominant generation of Th2 clones whose transfer both prevented induction of EAE and abrogated established disease. Since co-treatment with anti-IL-4 antibody prevented disease amelioration, costimulatory molecules may directly affect initial cytokine secretion. Thus, interaction of B7-1 and B7-2 with shared counterreceptors CD28 and CTLA-4 results in very different outcomes in clinical disease by influencing commitment of precursors to a Th1 or Th2 lineage.
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              TH17 cells mediate steroid-resistant airway inflammation and airway hyperresponsiveness in mice.

              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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                Author and article information

                Journal
                Med Sci Monit
                Med. Sci. Monit
                Medical Science Monitor
                Medical Science Monitor : International Medical Journal of Experimental and Clinical Research
                International Scientific Literature, Inc.
                1234-1010
                1643-3750
                2018
                16 May 2018
                : 24
                : 3220-3229
                Affiliations
                [1 ]Department of Respiratory Medicine, Children’s Hospital of Chongqing Medical University, Chongqing, P.R. China
                [2 ]Department of Urology, Children’s Hospital of Chongqing Medical University, Chongqing, P.R. China
                Author notes
                Corresponding Author: Zhou Fu, e-mail: fuzhoucqmu@ 123456126.com
                [A]

                Study Design

                [B]

                Data Collection

                [C]

                Statistical Analysis

                [D]

                Data Interpretation

                [E]

                Manuscript Preparation

                [F]

                Literature Search

                [G]

                Funds Collection

                Article
                905202
                10.12659/MSM.905202
                5985709
                29768397
                1a11746e-79e6-4224-a035-b3a9964cb67d
                © Med Sci Monit, 2018

                This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International ( CC BY-NC-ND 4.0)

                History
                : 07 May 2017
                : 22 June 2017
                Categories
                Animal Study

                anti-asthmatic agents,antigens, differentiation, t-lymphocyte,endotoxins

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