The Overexpression of Heparin-Binding Epidermal Growth Factor Is Responsible for Th17-Induced Airway Remodeling in an Experimental Asthma Model

Wang, Qing; Li, Hequan; Yao, Yinan; Xia, Dajing; Zhou, Jianying

doi:10.4049/jimmunol.0901490

Cited by 72 publications

(76 citation statements)

References 49 publications

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“…Prolonged OVA exposure has been demonstrated to lead to prominent changes similar to those previously reported in airway remodeling in sensitized mice (13,17). In our experimental mouse model, the density of pulmonary microvasculature increased progressively with prolonged allergen challenge (Fig.…”

Section: Resultssupporting

confidence: 83%

“…In our previous study, increased Th17 cells and IL-17 production were observed along with increased collagen deposition, airway smooth muscle mass, and mucous hypertrophy in a mouse model of asthmatic airway remodeling (13). In this study, we further investigated the role of Th17 cell and its cytokines in airway vascular remodeling, mobilization, and recruitment of EPCs, as well as proliferation and tubule formation by PMVECs.…”

mentioning

confidence: 87%

“…Th17 cells were differentiated from naive CD4 + T cells in the presence of the required stimulating factors and associated Ig, according to a previously reported protocol (13). Naive CD4 + T cells were acquired from the spleens of C57BL/6 mice using anti-CD4 microbeads and a magnetic sorter (MACS; Miltenyi Biotec, Auburn, CA).…”

Section: Th17 Cell Generation and Adoptive Transfermentioning

confidence: 99%

“…For detecting Th17 cells, cells prepared from lungs were stimulated with 50 ng/ml PMA (BioVision, Mountain View, CA) and 500 ng/ml ionomycin (Fermentek, Jerusalem, Israel) in the presence of GolgiStop (eBioscience) for 4 h. Later, cells were surfacestained for CD4 (eBioscience), permeabilized with Cytofix/Cytoperm (eBioscience), washed, and intracellularly stained with PE-labeled anti-IL-17 (BD Biosciences). Rat IgG of the corresponding class (eBioscience) was used as an isotype control (13). Flow-cytometry acquisition was performed using a FACSCalibur instrument (BD Biosciences), and the results were analyzed with Cell Quest software (BD Biosciences).…”

Section: Flow Cytometrymentioning

confidence: 99%

“…After treatment with IL-17A for 1-12 h, cell lysates were prepared and examined by Western blot analysis as described previously (13). Blots were probed with anti-phospho-AKT Ab (1:1000; Cell Signaling Technology, Beverly, MA) and anti-AKT Ab (1:1000; Cell Signaling Technology) overnight at 4˚C.…”

Section: Western Blot Analysismentioning

confidence: 99%

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IL-17A, But Not IL-17F, Is Indispensable for Airway Vascular Remodeling Induced by Exaggerated Th17 Cell Responses in Prolonged Ovalbumin-Challenged Mice

Gao

et al. 2015

The Journal of Immunology

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We previously demonstrated an essential role of Th17 cells in excessive mucous secretion and airway smooth muscle proliferation in a prolonged OVA-challenged C57BL/6 mouse model. However, the impact of Th17 cells in vascular remodeling, another characteristic feature of airway remodeling in asthma, remains elusive. This issue was further investigated in this study. The time-course experiments showed that progressively increasing levels of Th17 cells and IL-17A (not IL-17F) in the lungs of prolonged allergen-challenged mice were positively correlated with microvessel density in peribronchial tissues. In addition, exaggerated airway vascular remodeling in this mouse model was exacerbated by airway administration of IL-17A or adoptive transfer of Th17 cells. This effect was dramatically alleviated by the administration of anti–IL-17A Ab, but not anti–IL-17F Ab. Boyden chamber assays indicated that IL-17A accelerates endothelial progenitor cell (EPC) migration. Furthermore, EPC accumulation in the airways of allergen-exposed mice after adoptive transfer of Th17 cells was eliminated by blockade of IL-17A. We found that IL-17A promoted tubule-like formation rather than proliferation of pulmonary microvascular endothelia cells (PMVECs) in vitro. In addition, IL-17A induced PMVEC tube formation via the PI3K/AKT1 pathway, and suppression of the PI3K pathway markedly reduced the formation of tubule-like structures. Collectively, our results indicate that Th17 cells contribute to the airway vascular remodeling in asthma by mediating EPC chemotaxis, as well as PMVEC tube formation, via IL-17A rather than IL-17F.

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Section: Resultssupporting

confidence: 83%

mentioning

confidence: 87%

Section: Th17 Cell Generation and Adoptive Transfermentioning

confidence: 99%

Section: Flow Cytometrymentioning

confidence: 99%

Section: Western Blot Analysismentioning

confidence: 99%

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IL-17A, But Not IL-17F, Is Indispensable for Airway Vascular Remodeling Induced by Exaggerated Th17 Cell Responses in Prolonged Ovalbumin-Challenged Mice

Gao

et al. 2015

The Journal of Immunology

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Asthma: The importance of dysregulated barrier immunity

2013

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Chronic asthma is an inflammatory disease of the airway wall that leads to bronchial smooth muscle hyperreactivity and airway obstruction, caused by inflammation, goblet cell metaplasia, and airway wall remodeling. In response to allergen presentation by airway DCs, T-helper lymphocytes of the adaptive immune system control many aspects of the disease through secretion of IL-4, IL-5, IL-13, IL-17, and IL-22, and these are counter- Adaptive immunity in asthma: more than a Th2-mediated disorderChronic asthma is an inflammatory disease of the airway wall. The earliest studies on asthma pathology found that CD4 + T lymphocytes were present in asthma biopsies. Over the past 30 years, the Th1-Th2 paradigm has dominated the asthma research field. The immune response to inhaled allergens (such as house dust mite (HDM), cockroach, pollen grains, or fungal spores) is characterized by an aberrant Th2 lymphocyte response that has the potential to cause the features of asthma. Th2-type cytokines cause airway eosinophilia (IL-5), goblet cell metaplasia (GCM; IL-4 and IL-13),

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A recombinant protein rLZ-8, originally extracted from Ganoderma lucidum, ameliorates OVA-induced lung inflammation by regulating Th17/Treg balance

Liu

Qiu

Wang

et al. 2020

Journal of Leukocyte Biology

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Asthma is one of the most common chronic and inflammatory respiratory diseases, which is estimated to affect 1-10% of the population in different regions across the world. Previous studies have shown that recombinant Ling-Zhi 8 (rLZ-8), an immunoregulatory protein originally extracted from Ganoderma lucidum, plays multiple roles in regulating murine immune cells, including T cells. Here, we examined whether rLZ-8 would ameliorate pulmonary inflammation in a model of asthma-like mice. We found that rLZ-8 significantly inhibited the lung inflammation and reduced infiltration of inflammatory cells, including dendritic cells and eosinophils, in OVAinduced asthmatic mice. It also deceased IL-17A level but increased IL-10 level in bronchoalveolar lavage fluid (BALF) while reducing ROR t mRNA expression and enhancing Foxp3 mRNA level in the lung tissue. Flow cytometry studies demonstrated that rLZ-8 remarkably down-regulated Th17 cells but upregulated Foxp3 + regulatory T (Treg) cells, rather than influencing Th1 versus Th2 cells. Experiments in vitro also showed that rLZ-8 suppressed murine CD3 + T cell proliferation and reduced the frequency of Th17 cells while promoting the differentiation of CD4 + Foxp3 + Tregs. Moreover, rIL-8 similarly altered human Th17/Treg generation or their balance in vitro. Finally, we found that rLZ-8 suppressed signaling pathways of both STAT3 and NF-B (P100/P52) in murine lung tissue as well as cultured T cells. Thus, we have demonstrated that rLZ-8 attenuates pulmonary inflammation through regulating the balance of Th17/Treg cells in OVA-induced asthmatic mice and that rLZ-8 may be a potential therapeutic agent for the treatment of asthma in clinic. K E Y W O R D S herbal ingredient, pulmonary inflammation, Th cell, treg 1 INTRODUCTION Asthma, a chronic inflammatory airway disease associated with reversible airflow obstruction and persistent airway hyperresponsiveness, is a major public health problem that affects 300 million people worldwide. Although asthma is relatively well controlled by the most Abbreviations: BALF, bronchoalveolar lavage fluid; DC, dendritic cell; DEX, dexamethasone; rLZ-8, recombinant Ling-Zhi protein-8; Treg, regulatory T cell. effective first-line treatment, including inhaled corticosteroids, an estimated 40% of asthmatics fail to respond to corticosteroid and show no improvement in airway function. 1 In addition, various side effects resulting from the long-term use of these agents necessitate alternative therapeutic options. Allergen-specific CD4 + T cells have been shown to play a key role in the development of asthma. 2 In patients with the mild to moderate asthma, the classic mode of onset is that specific IgE Abs of B cells induced by CD4 + Th2 cells mediate immune responses and

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The Overexpression of Heparin-Binding Epidermal Growth Factor Is Responsible for Th17-Induced Airway Remodeling in an Experimental Asthma Model

Abstract: Material

Cited by 72 publications

References 49 publications

IL-17A, But Not IL-17F, Is Indispensable for Airway Vascular Remodeling Induced by Exaggerated Th17 Cell Responses in Prolonged Ovalbumin-Challenged Mice

IL-17A, But Not IL-17F, Is Indispensable for Airway Vascular Remodeling Induced by Exaggerated Th17 Cell Responses in Prolonged Ovalbumin-Challenged Mice

Asthma: The importance of dysregulated barrier immunity

A recombinant protein rLZ-8, originally extracted from Ganoderma lucidum, ameliorates OVA-induced lung inflammation by regulating Th17/Treg balance

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