The CXCL10/CXCR3 Axis Mediates Human Lung Mast Cell Migration to Asthmatic Airway Smooth Muscle

Brightling, Christopher E.; Ammit, Alaina J.; Kaur, Davinder; Black, Judith L.; Wardlaw, Andrew J.; Hughes, JM; Bradding, Peter

doi:10.1164/rccm.200409-1220oc

Cited by 266 publications

(314 citation statements)

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“…Indeed, a recent study has demonstrated that tryptase-stimulated human ASM cells attract mast cells through the release of TGF-␤1 in addition to SCF, and that both factors are localized to ASM in asthmatic airways (11). Another recent study has shown that the chemokine CXCL10 (IFN-␥-inducible protein 10) is expressed preferentially by asthmatic ASM cells, and its receptor CXCR3 is most abundantly expressed on mast cells in asthmatic ASM, suggesting that interactions between ASM-derived CXCL10 and mast cell-expressed CXCR3 may play a key role in mast cell migration into the ASM bundles in asthma (40). Tryptase cleavage of eotaxin and RANTES may therefore not have an impact on mast cell microlocalization in asthmatic ASM.…”

Section: Discussionmentioning

confidence: 99%

Mast Cell β-Tryptase Selectively Cleaves Eotaxin and RANTES and Abrogates Their Eosinophil Chemotactic Activities

Pang

Nie

Corbett

et al. 2006

The Journal of Immunology

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Recent studies have shown that a lack of eosinophils in asthmatic airway smooth muscle (ASM) bundles in contrast to the large number of mast cells is a key feature of asthma. We hypothesized that this is caused by β-tryptase, the predominant mast cell-specific protease, abrogating the eosinophil chemotactic activities of ASM cell-derived eosinophil chemoattractants such as eotaxin and RANTES. We studied the effect of β-tryptase on the immunoreactivities of human ASM cell-derived and recombinant eotaxin and other recombinant chemokines that are known to be produced by human ASM cells. We report in this study that purified β-tryptase markedly reduced the immunoreactivity of human ASM cell-derived and recombinant eotaxin, but had no effect on eotaxin mRNA expression. The effect was mimicked by recombinant human β-tryptase in the presence of heparin and was reversed by heat inactivation and the protease inhibitor leupeptin, suggesting that the proteolytic activity of tryptase is required. β-Tryptase also exerted similar effects on recombinant RANTES, but not on the other chemokines and cytokines that were screened. Furthermore, a chemotaxis assay revealed that recombinant eotaxin and RANTES induced eosinophil migration concentration-dependently, which was abrogated by pretreatment of these chemokines with β-tryptase. Another mast cell protease chymase also markedly reduced the immunoreactivity of eotaxin, but had no effect on RANTES and other chemokines and did not affect the influence of β-tryptase on RANTES. These findings suggest that mast cell β-tryptase selectively cleaves ASM-derived eotaxin and RANTES and abrogates their chemotactic activities, thus providing an explanation for the eosinophil paucity in asthmatic ASM bundles.

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Section: Discussionmentioning

confidence: 99%

Mast Cell β-Tryptase Selectively Cleaves Eotaxin and RANTES and Abrogates Their Eosinophil Chemotactic Activities

Pang

Nie

Corbett

et al. 2006

The Journal of Immunology

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“…The location of mast cells within the ASM is believed to facilitate hyper- [26,27]. ASM cells also produce SCF, which itself induces mast cell recruitment, differentiation and survival [28].…”

Section: Asthmamentioning

confidence: 99%

The mast cell and allergic diseases: role in pathogenesis and implications for therapy

Brown

Wilson

Metcalfe

2007

Clin Experimental Allergy

243

184

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SummaryMast cells have long been recognized for their role in the genesis of allergic inflammation; and more recently for their participation in innate and acquired immune responses. Mast cells reside within tissues including the skin and mucosal membranes, which interface with the external environment; as well as being found within vascularized tissues next to nerves, blood vessels and glandular structures. Mast cells have the capability of reacting both within minutes and over hours to specific stimuli, with local and systemic effects. Mast cells express the high affinity IgE receptor (FceRI) and upon aggregation of FceRI by allergen-specific IgE, mast cells release and generate biologically active preformed and newly synthesized mediators which are involved in many aspects of allergic inflammation. While mast cells have been well documented to be essential for acute allergic reactions, more recently the importance of mast cells in reacting through pattern recognition receptors in innate immune responses has become recognized. Moreover, as our molecular understanding of the mast cell has evolved, novel targets for modulation have been identified with promising therapeutic potential.

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“…ASMs from individuals with asthma exhibit increased synthetic capacity (8,9), mitochondrial biogenesis (10), altered calcium homeostasis (10,11), and in some reports (10)(11)(12), but not all (13,14), increased proliferation. Critically, there is emerging evidence that ASM from individuals with asthma is hypercontractile as demonstrated by an increased velocity of contraction in response to electrical field stimulation at the single-cell level (15) and in cell populations using gel contraction assays (16).…”

mentioning

confidence: 99%

Increased Nicotinamide Adenine Dinucleotide Phosphate Oxidase 4 Expression Mediates Intrinsic Airway Smooth Muscle Hypercontractility in Asthma

Sutcliffe

Hollins²,

Gomez³

et al. 2012

Am J Respir Crit Care Med

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Rationale: Asthma is characterized by disordered airway physiology as a consequence of increased airway smooth muscle contractility. The underlying cause of this hypercontractility is poorly understood. Objectives: We sought to investigate whether the burden of oxidative stress in airway smooth muscle in asthma is heightened and mediated by an intrinsic abnormality promoting hypercontractility. Methods: We examined the oxidative stress burden of airway smooth muscle in bronchial biopsies and primary cells from subjects with asthma and healthy controls. We determined the expression of targets implicated in the control of oxidative stress in airway smooth muscle and their role in contractility. Measurements and Main Results: We found that the oxidative stress burden in the airway smooth muscle in individuals with asthma is heightened and related to the degree of airflow obstruction and airway hyperresponsiveness. This was independent of the asthmatic environment as in vitro primary airway smooth muscle from individuals with asthma compared with healthy controls demonstrated increased oxidative stress-induced DNA damage together with an increased production of reactive oxygen species. Genome-wide microarray of primary airway smooth muscle identified increased messenger RNA expression in asthma of NADPH oxidase (NOX) subtype 4. This NOX4 overexpression in asthma was supported by quantitative polymerase chain reaction, confirmed at the protein level. Airway smooth muscle from individuals with asthma exhibited increased agonist-induced contraction. This was abrogated by NOX4 small interfering RNA knockdown and the pharmacological inhibitors diphenyleneiodonium and apocynin. Conclusions: Our findings support a critical role for NOX4 overexpression in asthma in the promotion of oxidative stress and consequent airway smooth muscle hypercontractility. This implicates NOX4 as a potential novel target for asthma therapy.Keywords: asthma; airway smooth muscle; airway hyperresponsiveness; NOX4; SOD2 Asthma affects over 300 million people worldwide. Importantly, asthma control is suboptimal in about half of sufferers, and 10% are refractory to current antiinflammatory and bronchodilator therapies (1, 2). There is therefore an urgent need for new therapies. Asthma is characterized by variable airflow obstruction and airway hyperresponsiveness as a consequence of increased airway smooth muscle contractility (1, 2). This heightened airway smooth muscle (ASM) contraction is considered to be largely due to the local asthmatic milieu with infiltration by inflammatory cells, in particular eosinophils and T cells, into the submucosa (2-4), to mast cells in the ASM bundle (4, 5), and to up-regulation of Th2 cytokines (6, 7).Interestingly, there is an increasing body of evidence that ASM is fundamentally altered in asthma compared with healthy controls, suggesting that abnormalities in these structural cells may also play a critical role in the development of the abnormal physiology in asthma and may contribute to the persistent airway ...

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The CXCL10/CXCR3 Axis Mediates Human Lung Mast Cell Migration to Asthmatic Airway Smooth Muscle

Cited by 266 publications

References 40 publications

Mast Cell β-Tryptase Selectively Cleaves Eotaxin and RANTES and Abrogates Their Eosinophil Chemotactic Activities

Mast Cell β-Tryptase Selectively Cleaves Eotaxin and RANTES and Abrogates Their Eosinophil Chemotactic Activities

The mast cell and allergic diseases: role in pathogenesis and implications for therapy

Increased Nicotinamide Adenine Dinucleotide Phosphate Oxidase 4 Expression Mediates Intrinsic Airway Smooth Muscle Hypercontractility in Asthma

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