Severe asthma in humans and mouse model suggests a CXCL10 signature underlies corticosteroid-resistant Th1 bias

Gauthier, Marc; Chakraborty, Krishnendu; Oriss, Timothy B.; Raundhal, Mahesh; Das, Sudipta; Chen, Jie; Huff, Rachael; Sinha, Ayan; Fajt, Merritt L.; Ray, Prabir; Wenzel, Sally E.; Ray, Anuradha

doi:10.1172/jci.insight.94580

Cited by 91 publications

(82 citation statements)

References 59 publications

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“…We discovered that bethanechol-mediated airway hyperreactivity was associated with an increase in inflammatory transcripts (IL17A, IL1A, IL8, CXCL10, IFNγ) that are of known or proposed significance in asthma pathogenesis [19–22]. Although we did not anticipate this finding, previous studies have suggested a pro-inflammatory role for cholinergic signaling in the airway.…”

Section: Resultsmentioning

confidence: 65%

Solitary Cholinergic Stimulation Induces Airway Hyperreactivity and Transcription of Distinct Pro-inflammatory Pathways

Reznikov

Meyerholz

Kuan

et al. 2018

Lung

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Airway hyperreactivity is a hallmark feature of asthma and can be precipitated by airway insults, such as ozone exposure or viral infection. A proposed mechanism linking airway insults to airway hyperreactivity is augmented cholinergic transmission. In the current study, we tested the hypothesis that acute potentiation of cholinergic transmission is sufficient to induce airway hyperreactivity. We atomized the cholinergic agonist bethanechol to neonatal piglets and forty-eight hours later measured airway resistance. Bethanechol-treated piglets displayed increased airway resistance in response to intravenous methacholine compared to saline-treated controls. In the absence of an airway insult, we expected to find no evidence of airway inflammation; however, transcripts for several asthma-associated cytokines, including IL17A, IL1A, and IL8, were elevated in the tracheas of bethanechol-treated piglets. In the lungs, prior bethanechol treatment increased transcripts for IFNγ and its downstream target CXCL10. These findings suggest that augmented cholinergic transmission is sufficient to induce airway hyperreactivity, and raise the possibility that cholinergic-mediated regulation of pro-inflammatory pathways might contribute.

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Section: Resultsmentioning

confidence: 65%

Solitary Cholinergic Stimulation Induces Airway Hyperreactivity and Transcription of Distinct Pro-inflammatory Pathways

Reznikov

Meyerholz

Kuan

et al. 2018

Lung

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“…Both mouse and human studies suggest that effects of IFN‐γ on MCs may importantly influence multiple aspects of the pathology of certain forms of asthma, particularly those associated with high levels of neutrophil infiltration of the airways and certain forms of severe asthma . However, in such settings, MCs are more likely to represent important targets of IFN‐γ rather than critical sources of this cytokine.…”

Section: Mast Cell‐derived Cytokines Growth Factors and Mitogensmentioning

confidence: 99%

Mast cells as sources of cytokines, chemokines, and growth factors

Mukai

Tsai

Saito

et al. 2018

Immunological Reviews

514

508

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Mast cells are hematopoietic cells that reside in virtually all vascularized tissues and that represent potential sources of a wide variety of biologically active secreted products, including diverse cytokines and growth factors. There is strong evidence for important non-redundant roles of mast cells in many types of innate or adaptive immune responses, including making important contributions to immediate and chronic IgE-associated allergic disorders and enhancing host resistance to certain venoms and parasites. However, mast cells have been proposed to influence many other biological processes, including responses to bacteria and virus, angiogenesis, wound healing, fibrosis, autoimmune and metabolic disorders, and cancer. The potential functions of mast cells in many of these settings is thought to reflect their ability to secrete, upon appropriate activation by a range of immune or non-immune stimuli, a broad spectrum of cytokines (including many chemokines) and growth factors, with potential autocrine, paracrine, local, and systemic effects. In this review, we summarize the evidence indicating which cytokines and growth factors can be produced by various populations of rodent and human mast cells in response to particular immune or non-immune stimuli, and comment on the proven or potential roles of such mast cell products in health and disease.

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“…The authors suggested that IFN-γ-induced downregulation of secretory leukocyte protease inhibitor (SLPI) in AECs is responsible for increased AHR in severe asthma. The same group also suggested that corticosteroids may not only be inefficacious in these patients but may actually exacerbate the underlying inflammatory state through increased Th1 recruitment [67]. …”

Section: Introductionmentioning

confidence: 99%

Understanding Asthma Phenotypes, Endotypes, and Mechanisms of Disease

Kuruvilla

Lee

2018

Clinic Rev Allerg Immunol

732

719

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The model of asthma as a single entity has now been replaced by a much more complex biological network of distinct and interrelating inflammatory pathways. The term asthma is now considered an umbrella diagnosis for several diseases with distinct mechanistic pathways (endotypes) and variable clinical presentations (phenotypes). The precise definition of these endotypes is central to asthma management due to inherent therapeutic and prognostic implications. This review presents the molecular mechanisms behind the heterogeneity of airway inflammation in asthmatic patients. Asthma endotypes may be broadly regarded as type 2 (T2) high or T2-low. Several biologic agents have been approved for T2-high asthma, with numerous other therapeutics that are incipient and similarly targeted at specific molecular mechanisms. Collectively, these advances have shifted existing paradigms in the approach to asthma to tailor novel therapies.

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Severe asthma in humans and mouse model suggests a CXCL10 signature underlies corticosteroid-resistant Th1 bias

Cited by 91 publications

References 59 publications

Solitary Cholinergic Stimulation Induces Airway Hyperreactivity and Transcription of Distinct Pro-inflammatory Pathways

Solitary Cholinergic Stimulation Induces Airway Hyperreactivity and Transcription of Distinct Pro-inflammatory Pathways

Mast cells as sources of cytokines, chemokines, and growth factors

Understanding Asthma Phenotypes, Endotypes, and Mechanisms of Disease

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