STAT3 inhibition prevents lung inflammation, remodeling, and accumulation of Th2 and Th17 cells in a murine asthma model

Gavino, Aries; Nahmod, Karen; Bharadwaj, Uddalak; Makedonas, George; Tweardy, David J.

doi:10.1111/all.12937

Cited by 91 publications

(78 citation statements)

References 38 publications

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“…Th2 cytokines IL-4 and IL-13 can activate epithelial and endothelial cells and fibroblasts to produce eotaxin, a chemotaxin important for recruiting eosinophil from the airway microvessels into the lung tissue [35]. Recently, compelling evidences have demonstrated that Th17 cells are a major player to the pathogenesis of allergic airway inflammation, especially to severe asthma [22, 23, 29, 38–40]. The latter is often induced by infection and resistant to steroid therapy in patients [41].…”

Section: Discussionmentioning

confidence: 99%

Schistosoma japonicum infection downregulates house dust mite-induced allergic airway inflammation in mice

Qiu¹,

Fan²,

Yang³

et al. 2017

PLoS ONE

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The “hygiene hypothesis” is a theory try to explain the dramatic increases in the prevalence of autoimmune and allergic diseases over the past two to three decades in developed countries. According to this theory, reduced exposure to parasites and microorganisms in childhood is the main cause for the increased incidences of both T helper 1 (Th1)-mediated autoimmunity and Th2-mediated allergy. In this study, we investigated the impact of Schistosoma japonicum infection on the allergic airway inflammation induced by repeated intracheal inoculations of house dust mites (HDM), which is a Th17 and neutrophils dominant murine asthma model, mimicking severe asthma. We found that S. japonicum infection downregulated airway hyperresponsiveness. The infiltrating cells, Th17 and Th2 effector cytokines in the bronchoalveolar lavage (BAL) fluids and lungs were significantly reduced in the infected mice. Our findings indicated that S. japonicum infection was able to effectively inhibit host’s allergic airway inflammation, which may be related to the upregulated Treg cells upon infection. To our knowledge, it is the first study to reveal the impact of S. japonicum infection on house dust mite induced severe asthma. More in depth investigation is need to elucidate the underlying mechanisms.

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Section: Discussionmentioning

confidence: 99%

Schistosoma japonicum infection downregulates house dust mite-induced allergic airway inflammation in mice

Qiu¹,

Fan²,

Yang³

et al. 2017

PLoS ONE

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“…Studies in mouse models show that persistent IL-17 activation leads to increased collagen deposition, airway smooth muscle mass, and mucous hypertrophy in a mouse model of asthmatic airway remodeling [21]. More recently, we demonstrated that airway inflammation and remodeling in the murine house dust mite (HDM) model of asthma is accompanied by STAT3 activation within the lung and by increased lung levels of Th2- as well as Th17-type cytokines [22]. …”

Section: Stat3 and Asthmamentioning

confidence: 99%

“…We showed that systemic administration C188-9, abrogated HDM-induced STAT3 activation, airway inflammation, and remodeling. Inhibition of HDM-induced lung changes by C188-9 was accompanied by normalization of IL-4, IL-5, IL-13, and IL-17A cytokine levels, as well as prevention of HDM-induced increases in Th2 cells, Th17 cells, and IL-4- and IL-17A-producing non-T cells [22]. Available data suggest there may be a therapeutic advantage of targeting both Th2 and Th17 in asthma to maximize therapeutic efficacy [69], which C188-9 may be able to provide.…”

Section: Stat3 and Asthmamentioning

confidence: 99%

Contribution of STAT3 to Inflammatory and Fibrotic Diseases and Prospects for its Targeting for Treatment

Kasembeli

Bharadwaj

Robinson

et al. 2018

IJMS

136

119

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Signal transducer and activator of transcription (STAT) 3 plays a central role in the host response to injury. It is activated rapidly within cells by many cytokines, most notably those in the IL-6 family, leading to pro-proliferative and pro-survival programs that assist the host in regaining homeostasis. With persistent activation, however, chronic inflammation and fibrosis ensue, leading to a number of debilitating diseases. This review summarizes advances in our understanding of the role of STAT3 and its targeting in diseases marked by chronic inflammation and/or fibrosis with a focus on those with the largest unmet medical need.

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“…Th2 and Th17 inflammatory pathways seemed to be reciprocally regulated in asthma [41]. On the other hand, CpG-oligodeoxynucleotides [37], STAT3 inhibition [42], CB2 receptors on NK cells [31] or secretoglobin superfamily protein SCGB3A2 [33] suppressed allergen-induced asthma in mice. Thus, the investigated factors illustrate that asthma can be counterregulated by reinforcing tolerance or skewing Th2-based asthma towards Th1 or Th17.…”

Section: Introductionmentioning

confidence: 99%

Outstanding animal studies in allergy I. From asthma to food allergy and anaphylaxis

Jensen‐Jarolim

Pali‐Schöll

Roth‐Walter

2017

Current Opinion in Allergy &Amp; Clinical Immunology

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Purpose of reviewAnimal models published within the past 18 months on asthma, food allergy and anaphylaxis, all conditions of rising public health concern, were reviewed.Recent findingsWhile domestic animals spontaneously develop asthma, food allergy and anaphylaxis, in animal models, divergent sensitization and challenge routes, dosages, intervals and antigens are used to induce asthmatic, food allergic or anaphylactic phenotypes. This must be considered in the interpretation of results. Instead of model antigens, gradually relevant allergens such as house dust mite in asthma, and food allergens like peanut, apple and peach in food allergy research were used. Novel engineered mouse models such as a mouse with a T-cell receptor for house dust mite allergen Der p 1, or with transgenic human hFcγR genes, facilitated the investigation of single molecules of interest. Whole-body plethysmography has become a state-of-the-art in-vivo readout in asthma research. In food allergy and anaphylaxis research, novel techniques were developed allowing real-time monitoring of in-vivo effects following allergen challenge. Networks to share tissues were established as an effort to reduce animal experiments in allergy which cannot be replaced by in-vitro measures.SummaryNatural and artificial animal models were used to explore the pathophysiology of asthma, food allergy and anaphylaxis and to improve prophylactic and therapeutic measures. Especially the novel mouse models mimicking molecular aspects of the complex immune network in asthma, food allergy and anaphylaxis will facilitate proof-of-concept studies under controlled conditions.

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STAT3 inhibition prevents lung inflammation, remodeling, and accumulation of Th2 and Th17 cells in a murine asthma model

Abstract: HDM-induced airway inflammation, remodeling, and Th2/Th17-type cell accumulation involve STAT3 activation that can be prevented by C188-9 treatment.

Cited by 91 publications

References 38 publications

Schistosoma japonicum infection downregulates house dust mite-induced allergic airway inflammation in mice

Schistosoma japonicum infection downregulates house dust mite-induced allergic airway inflammation in mice

Contribution of STAT3 to Inflammatory and Fibrotic Diseases and Prospects for its Targeting for Treatment

Outstanding animal studies in allergy I. From asthma to food allergy and anaphylaxis

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