Airway infiltration of CD4+ CCR6+ Th17 type cells associated with chronic cigarette smoke induced airspace enlargement

Harrison, Oliver J.; Foley, Joseph; Bolognese, Brian; Long, Edward R.; Podolin, Patricia L.; Walsh, Patrick

doi:10.1016/j.imlet.2008.07.011

Cited by 81 publications

(52 citation statements)

References 46 publications

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“…In addition to allergen-induced airway inflammation, a crucial role for CCL20 has been demonstrated in cigarette smoke-induced airway infiltration of neutrophils, T-lymphocytes and dendritic cells in a mouse model of chronic obstructive pulmonary disease (COPD) [24]. Importantly, both Th17-mediated neutrophilic airway inflammation and cigarette smoking have been related to glucocorticoid insensitivity in asthma [25] and smoking has been shown to induce airway infiltration of both neutrophils and Th17-type cells [26]. Thus, we propose a novel paradigm for the development of glucocorticoid-insensitive airway inflammation in both asthma and COPD, where glucocorticoids enhance CCL20 release, inducing airway infiltration of CCR6 + neutrophils and Th17 cells.…”

Section: Discussionmentioning

confidence: 99%

Glucocorticoids induce the production of the chemoattractant CCL20 in airway epithelium

et al. 2014

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Th17-mediated neutrophilic airway inflammation has been implicated in decreased response to glucocorticoids in asthma. We aimed to investigate the effect of glucocorticoids on the airway epithelial release of the neutrophilic and Th17-cell chemoattractant CCL20.We studied CCL20 and CXCL8 sputum levels in asthmatic subjects using inhaled glucocorticoids or not, and the effect of budesonide on CCL20 and CXCL8 production in primary bronchial epithelial cells. The mechanism behind the effect of budesonide-induced CCL20 production was studied in 16HBE14o-cells using inhibitors for the glucocorticoid receptor, intracellular pathways and metalloproteases.We observed higher levels of CCL20, but not CXCL8, in the sputum of asthmatics who used inhaled glucocorticoids. CCL20 levels correlated with inhaled glucocorticoid dose and sputum neutrophils. Budesonide increased tumour necrosis factor (TNF)-a-induced CCL20 by primary bronchial epithelium, while CXCL8 was suppressed. In 16HBE14o-cells, similar effects were observed at the CCL20 protein and mRNA levels, indicating transcriptional regulation. Although TNF-a-induced CCL20 release was dependent on the ERK, p38 and STAT3 pathways, the increase by budesonide was not. Inhibition of glucocorticoid receptor or ADAM17 abrogated the budesonide-induced increase in CCL20 levels.We show that glucocorticoids enhance CCL20 production by bronchial epithelium, which may constitute a novel mechanism in Th17-mediated glucocorticoid-insensitive inflammation in asthma. @ERSpublications Glucocorticoids enhance production of CCL20 by airway epithelial cells: a mechanism of inflammation in asthma?

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Section: Discussionmentioning

confidence: 99%

Glucocorticoids induce the production of the chemoattractant CCL20 in airway epithelium

et al. 2014

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“…Recent findings suggest that a crucial component of COPD is inappropriate T cell-mediated immune responses in time of onset, intensity, and target (77)(78)(79)(80)(81)(82). Direct evidence for the critical role of T cells, both Th1 and Th2, is provided by mice with transgenic knock-in of IFN-g and IL-13, in which emphysematous changes were predictably and massively induced (83).…”

Section: Immune System Changes In Copdmentioning

confidence: 99%

The Aging Immune System and Its Relationship to the Development of Chronic Obstructive Pulmonary Disease

Sharma¹,

Hanania²,

Shim³

2009

Proceedings of the American Thoracic Society

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Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease of the lungs that usually manifests late in life. Physiologic and immunologic changes that occur in COPD often mimic changes seen in the aging lung. This has led some to characterize COPD as an ''accelerated aging phenotype.'' At the molecular level, COPD and aging share common mechanisms and are associated with significant dysregulation of the immune systems. Aging and COPD are characterized by increases in proinflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor (TNF)-a, which are implicated in aging-related inflammatory diseases and correlate with degree of obstruction in COPD. There is an age-dependent decline in naïve T cells with oligoclonal expansion of CD8 1 CD28 null T cells from chronic antigenic stimulation. The increase in CD8 1 CD28 null T regulatory cells inhibits antigen-specific CD4 1 T cell responses, leading to a decline in adaptive immune response. To compensate for the decline in the adaptive immune function there is a paradoxical up-regulation of innate immune system resulting in a proinflammatory state. The dysregulated adaptive immune system with activated innate immune responses seen with aging results in recruitment and retention of neutrophils, macrophages, and CD4 1 and CD8 1 T cells in the lungs of smokers with COPD. Once the inflammation is triggered, there is a selfperpetuating cascade of inflammation and lung parenchymal damage. This review will focus on how the aging immune system may contribute to COPD development later in life in susceptible individuals.

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“…It is tempting to speculate that Th17 cells play a role in disease pathogenesis given the role of IL-17 in promoting neutrophil chemotaxis as well as its reported ability to stimulate mucin production from respiratory epithelium (41,42). It is also noteworthy that Th17 cells in the airways of emphysematous mice express the chemokine receptor CCR6 (40). CCR6 deficient mice have previously been found to be protected from cigarette smoke induced pulmonary inflammation and airspace enlargement perhaps indicating an important role for Th17 cells (29).…”

Section: T Cellsmentioning

confidence: 99%

Chronic Obstructive Pulmonary Disease: Evidence for an Autoimmune Component

Stefańska

Walsh

2009

Cell Mol Immunol

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Chronic obstructive pulmonary disease (COPD) is characterized by an irreversible limitation on pulmonary airflow associated with chronic inflammation and mucous hypersecretion (chronic bronchitis) and/or the pathological destruction of alveolar airspaces leading to emphysema. COPD, predominantly as a result of tobacco smoke exposure, represents the fourth leading cause of mortality worldwide and its prevalence is increasing. Despite this, much of the basic mechanisms which contribute to disease progression remain to be elucidated and current therapeutic approaches are, for the most part, based upon alleviating patient symptoms (bronchodilators) as opposed to treating the underlying pathological mechanisms triggered in response to cigarette smoke exposure. The classic disease paradigm suggests that an imbalance of pulmonary matrix proteases versus anti-proteases underlies the tissue destruction and inflammation associated with COPD. However, there is a growing appreciation of the complex and multifaceted nature of the pathological mechanisms associated with disease progression. Recently, there has been mounting evidence indicating that COPD patients exhibit many of the characteristics of a classical autoimmune response. We will discuss current evidence in support of this paradigm and outline how future therapeutic approaches may be tailored to address this. Cellular & Molecular Immunology. 2009;6(2):81-86.

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Airway infiltration of CD4+ CCR6+ Th17 type cells associated with chronic cigarette smoke induced airspace enlargement

Cited by 81 publications

References 46 publications

Glucocorticoids induce the production of the chemoattractant CCL20 in airway epithelium

Glucocorticoids induce the production of the chemoattractant CCL20 in airway epithelium

The Aging Immune System and Its Relationship to the Development of Chronic Obstructive Pulmonary Disease

Chronic Obstructive Pulmonary Disease: Evidence for an Autoimmune Component

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