Dopamine D1-Like Receptor Antagonist Attenuates Th17-Mediated Immune Response and Ovalbumin Antigen-Induced Neutrophilic Airway Inflammation

Nakagome, Kazuyuki; Imamura, Mitsuru; Okada, Hirokazu; Kawahata, K.; Inoue, Tsutomu; Hashimoto, Kumiko; Harada, Hiroaki; Higashi, Taishi; Takagi, Ryukichi; Nakano, Kazuhisa; Hagiwara, Koichi; Kanazawa, Minoru; Dohi, Makoto; Nagata, Michio; Matsushita, Sho

doi:10.4049/jimmunol.1001274

Cited by 72 publications

(42 citation statements)

References 58 publications

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“…Immune-modulation therapies, including antigen desensitization, have been applied to asthmatic patients with modest success [44]. In animal models of airway inflammation, autoimmune encephalomyelitis, nephrotoxic serum nephritis, and rheumatoid arthritis, an antagonist to the dopamine receptor has been reported to attenuate DC function and thus the immunological response [28,45-47]. Our findings extend this concept and indicate for the first time that an LABA can directly suppress the immunological response in vivo .…”

Section: Discussionsupporting

confidence: 63%

“…Crosstalk between TLR4 and β2 ADR transduction pathways in DCs was demonstrated in vitro and in vivo [27]. Matsushita and colleagues reported that dopamine D1-like antagonists attenuate the Th17-mediated immune response through DCs and airway inflammation [28]. Therefore, we hypothesized that a β2 ADR agonist has inhibitory effects in allergic airway inflammation.…”

Section: Discussionmentioning

confidence: 99%

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β2 adrenergic agonist attenuates house dust mite-induced allergic airway inflammation through dendritic cells

et al. 2014

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BackgroundLong-acting β2 adrenergic agonists (LABAs) are commonly used combined with inhaled corticosteroids (ICS) to treat asthmatic patients. Previous reports suggest that LABAs have an anti-inflammatory effect in bronchial asthma, and this should be further investigated. The aim of this study was to investigate whether LABAs inhibit allergic airway inflammation and how this occurs.ResultsWe assessed the effect of the LABA formoterol (FORM) on inflammatory cell responses in airway, lung and regional lymph nodes, using an HDM-induced murine allergic asthma model in vivo. The effect of FORM on cytokine production from bone marrow derived dendritic cells (BMDCs) stimulated with HDM was evaluated in vitro. Adoptive transfer of BMDCs pulsed with HDM in the presence or absence of FORM to naïve mice was performed and the inflammatory response to subsequent HDM challenge was analyzed. FORM treatment suppressed HDM-induced changes and caused an increase in the number of eosinophils and neutrophils in bronchoalveolar lavage. The concentration of IL-4 and IL-17 in lung tissue homogenate was elevated and led to an accumulation of IL-4, IL-13, IL-5 and IL-17 producing cells in regional lymph nodes. FORM inhibited the production of IL-6 and IL-23 from BMDCs stimulated with HDM in vitro, and enhanced IL-10 production. The BMDCs adoptive transfer experiment indicated that dendritic cells mediate the effect of FORM, since FORM treatment of BMDCs in vitro attenuated airway inflammation.ConclusionThese results suggested that FORM modulates dendritic cell function and attenuates Th2 and Th17 responses induced by HDM. Thus, we propose that the clinical significance of LABAs should be re-investigated taking into account these immune-modulating effects.

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Section: Discussionsupporting

confidence: 63%

Section: Discussionmentioning

confidence: 99%

β2 adrenergic agonist attenuates house dust mite-induced allergic airway inflammation through dendritic cells

et al. 2014

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“…BALF samples were obtained as before [28]. Mouse lungs were flushed via the trachea cannula with 0.8 ml PBS 3 times following the final OVA challenge.…”

Section: Methodsmentioning

confidence: 99%

CCL2/CCR2-Dependent Recruitment of Th17 Cells but Not Tc17 Cells to the Lung in a Murine Asthma Model

Wang¹,

Wang²,

Cao³

et al. 2015

Int Arch Allergy Immunol

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Background: Interleukin (IL)-17 has been implicated in the pathogenesis of asthma and the progression of airway inflammation. Here, we used a model of allergic asthma and found that the frequencies of IL-17-secreting T helper (Th)17 and CD8 (Tc)17 cells were both significantly increased, as was the expression of the CC chemokine receptor (CCR2) on the surface of these cells. CC chemokine ligand 2 (CCL2) has been shown to mediate the activation and recruitment of inflammatory cells in asthma, which are also skewed after ovalbumin (OVA) challenge. However, the role of CCL2 on Th17 cells and Tc17 cells in asthma has not been illuminated. Methods: Mice that were sensitized and challenged with OVA received anti-CCL2 antibody (Ab; 5 μg/day intratracheally) or CCR2 antagonist (RS504393, 2 mg/kg/day intraperitoneally) prior to the challenge. Some mice received an isotype control Ab or vehicle alone. We then assessed the effects of allergic asthma and anti-CCL2 Ab or CCR2 antagonist treatment on the levels of IL-17 and CCL2, the Th17 and Tc17 cell frequencies and lung tissue inflammation. Results: We demonstrated that CCL2 and IL-17 levels and the frequency of Th17 and Tc17 cells in lung tissues and bronchoalveolar lavage fluid increased in the asthma group compared with the normal control mice. Blocking the CCL2/CCR2 axis greatly reduced the Th17 but not the Tc17 cell frequency, and revealed a suppressive effect on airway inflammation. Conclusion: These findings indicate a role for the CCL2/CCR2 axis in mediating Th17 but not Tc17 cell migration during acute allergic airway inflammation.

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“…We designed a study to determine whether the D1-like-R antagonist, SCH23390, suppresses OVA-Ag-induced neutrophilic airway inflammation in OVA TCR-transgenic DO11.10 mice, and then sought to elucidate the mechanism of action [44]. Briefly, 6-week-old female DO11.10 mice were challenged with an aerosolized solution of 3% OVA or PBS for 10 min on days –2 to 0.…”

Section: Effect Of Dopamine D1-like Receptor Antagonist On Ova-inducementioning

confidence: 99%

Neutrophilic Inflammation in Severe Asthma

Nakagome

Matsushita

Nagata

2012

Int Arch Allergy Immunol

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127

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Neutrophils may play an important role in the pathogenesis of severe asthma. Their infiltration into the airway is increased. Interleukin (IL)-8 is involved in this process, and is actually upregulated in the airways of patients. We have observed that in the absence of eosinophil chemoattractants, neutrophils stimulated by IL-8 augment eosinophil trans-basement membrane migration by releasing superoxide anion, matrix metalloproteinase, leukotriene B₄ and platelet-activating factor. These findings suggest that IL-8-stimulated neutrophils could lead eosinophils to accumulate in the airways of asthmatic patients, which might be a mechanism for corticosteroid resistance in severe asthma. However, the mechanisms of IL-8 upregulation in the airway are not completely understood. Several studies suggest that IL-17 (or T helper 17 cells; Th17) is involved in the IL-8 upregulation observed in severe asthma. We clarified that dopamine induces Th17 differentiation through dopamine D1-like receptor (D1-like-R), and that the D1-like-R antagonist attenuates Th17-mediated diseases like experimental autoimmune encephalomyelitis. Furthermore, we demonstrated that a D1-like-R antagonist significantly suppressed ovalbumin (OVA)-induced neutrophilic airway inflammation in OVA T cell receptor-transgenic DO11.10 mice through inhibiting Th17-mediated immune responses. Therefore, dopamine D1-like-R antagonists could become useful for treating Th17-mediated neutrophil-dominant severe asthma. As inhaled corticosteroids are known to be less effective for controlling neutrophilic inflammation, a more effective therapeutic strategy for neutrophil-dominant asthma should still be elucidated.

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Dopamine D1-Like Receptor Antagonist Attenuates Th17-Mediated Immune Response and Ovalbumin Antigen-Induced Neutrophilic Airway Inflammation

Cited by 72 publications

References 58 publications

β2 adrenergic agonist attenuates house dust mite-induced allergic airway inflammation through dendritic cells

β2 adrenergic agonist attenuates house dust mite-induced allergic airway inflammation through dendritic cells

CCL2/CCR2-Dependent Recruitment of Th17 Cells but Not Tc17 Cells to the Lung in a Murine Asthma Model

Neutrophilic Inflammation in Severe Asthma

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