Bone marrow cell derived arginase I is the major source of allergen-induced lung arginase but is not required for airway hyperresponsiveness, remodeling and lung inflammatory responses in mice

Niese, Kathryn A.; Collier, Ann R.; Hajek, Amanda R; Cederbaum, Stephen D.; O’Brien, William E.; Wills‐Karp, Marsha; Rothenberg, Marc E.; Zimmermann, Nives

doi:10.1186/1471-2172-10-33

Cited by 25 publications

(42 citation statements)

References 55 publications

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“…However, the arginase inhibitor S-(2-boronoethyl)-L-cysteine did not affect inflammatory cell numbers or cytokine levels in BAL, and even further enhanced peribronchiolar and perivascular inflammation in another mouse model of acute allergic asthma [51]. Remarkably, arginase I from bone marrow-derived cells appeared not to be required for allergen-induced recruitment of inflammatory cells into the lung [52], which could indicate a role for arginase in structural cells, particularly the airway epithelium, in this process.…”

Section: Discussionmentioning

confidence: 90%

Increased arginase activity contributes to airway remodelling in chronic allergic asthma

Maarsingh

Dekkers²,

Zuidhof³

et al. 2011

European Respiratory Journal

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Airway remodelling, characterised by increased airway smooth muscle (ASM) mass, subepithelial fibrosis, goblet cell hyperplasia and mucus gland hypertrophy, is a feature of chronic asthma. Increased arginase activity could contribute to these features via increased formation of polyamines and L-proline downstream of the arginase product L-ornithine, and via reduced nitric oxide synthesis.Using the specific arginase inhitibor 2(S)-amino-6-boronohexanoic acid (ABH), we studied the role of arginase in airway remodelling using a guinea pig model of chronic asthma. Ovalbuminsensitised guinea pigs were treated with ABH or PBS via inhalation before each of 12 weekly allergen or saline challenges, and indices of arginase activity, and airway remodelling, inflammation and responsiveness were studied 24 h after the final challenge.Pulmonary arginase activity of repeatedly allergen-challenged guinea pigs was increased. Allergen challenge also increased ASM mass and maximal contraction of denuded tracheal rings, which were prevented by ABH. ABH also attenuated allergen-induced pulmonary hydroxyproline (fibrosis) and putrescine, mucus gland hypertrophy, goblet cell hyperplasia, airway eosinophilia and interleukin-13, whereas an increased L-ornithine/L-citrulline ratio in the lung was normalised. Moreover, allergen-induced hyperresponsiveness of perfused tracheae was fully abrogated by ABH.These findings demonstrate that arginase is prominently involved in allergen-induced airway remodelling, inflammation and hyperresponsiveness in chronic asthma.

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Section: Discussionmentioning

confidence: 90%

Increased arginase activity contributes to airway remodelling in chronic allergic asthma

Maarsingh

Dekkers²,

Zuidhof³

et al. 2011

European Respiratory Journal

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“…Similar to Relm-a, arginase I is another hallmark gene of alternatively activated macrophages and is induced after allergen challenge and helminth infection. Although the cationic amino-acid transporter-2 and arginase I were shown to play key roles in response to helminth infection (45,46), arginase I is not required for allergen-induced inflammation, AHR, or collagen deposition (47). Furthermore (and similar to our data demonstrating a role for Relm-a only in IL-13-induced responses but not allergen challenge), RNA interference targeting arginase 1 abrogated the development of IL-13-induced AHR (48), but not allergen-induced AHR (47).…”

Section: Discussionmentioning

confidence: 99%

Resistin-Like Molecule–α Regulates IL-13–Induced Chemokine Production but Not Allergen-Induced Airway Responses

Munitz

Cole²,

Karo‐Atar³

et al. 2012

Am J Respir Cell Mol Biol

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Resistin-like molecule a (Relm-a) is one of the most up-regulated gene products in allergen-and parasite-associated Th2 responses. Localized to alternatively activated macrophages, Relm-a was shown to exert an anti-inflammatory effect in parasite-induced Th2 responses, but its role in experimental asthma remains unexplored. Here, we analyzed the cellular source, the IL-4 receptors required to stimulate Relm-a production, and the role of Relm-a after experimental asthma induction by IL-4, IL-13, or multiple experimental regimes, including ovalbumin and Aspergillus fumigatus immunization. We demonstrate that Relm-a was secreted into the airway lumen, dependent on both the IL-13 receptora1 chain and likely the Type I IL-4 receptor, and differentially localized to epithelial cells and myeloid cells, depending on the specific cytokine or aeroallergen trigger. Studies performed with Retnla gene-targeted mice demonstrate that Relm-a was largely redundant in terms of inducing the infiltration of Th2 cytokines, mucus, and inflammatory cells into the lung. These results mirror the dispensable role that other alternatively activated macrophage products (such as arginase 1) have in allergen-induced experimental asthma and contrast with their role in the setting of parasitic infections. Taken together, our findings demonstrate the distinct utilization of IL-4/IL-13 receptors for the induction of Relm-a in the lungs. The differential regulation of Relm-a expression is likely determined by the relative expression levels of IL-4, IL-13, and their corresponding receptors, which are differentially expressed by divergent cells (i.e., epithelial cells and macrophages.) Finally, we identify a largely redundant functional role for Relm-a in acute experimental models of allergen-associated Th2 immune responses.Keywords: resistin-like molecule-a; asthma; IL-4; Asthma is a chronic and complex inflammatory disease of the airways characterized by airflow obstruction, mucus production, airway hyperresponsiveness (AHR), and airway inflammation. It is the most common chronic illness of childhood, affecting up to 20% of children and 7% of adults in Western countries, with a combined prevalence of approximately 300 million people worldwide (1).Asthmatic responses are associated with increased numbers of pulmonary inflammatory cells, including activated T-lymphocytes and eosinophils, which correlate with disease severity (2, 3). T-lymphocytes of the Th2 phenotype are thought to induce asthma through the secretion of an array of cytokines, and in particular, IL-4 and IL-13 (4, 5). These cytokines are produced at elevated concentrations in allergic tissue, and are central regulators of many hallmark features of the disease, such as the production of IgE, Th2 differentiation, eosinophilia, mucus hypersecretion, chemokine induction, and airway hyperresponsiveness (AHR) (6). Notably, IL-13 is considered more of an effector cytokine in the pathogenesis of allergic airway disease compared with IL-4 because AHR and mucus production are predominantly I...

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“…Comparable to our results, infiltration of the lungs with eosinophils and neutrophils was similar in mice with or without Arg1 ablation in hematopoietic cells. Lung function was assessed with the airway pressuretime index, which is less sensitive to changes in peripheral lung function (45) and may explain why no differences in lung function were found in that study (39).…”

mentioning

confidence: 80%

“…Recently, the effects of macrophagespecific Arg1 deficiency on lung function and inflammation were studied in OVA/OVA-treated wild-type mice after bone marrow transplantation with constitutively Arg1-deficient cells (39), a procedure that also involves Arg1 elimination in all bone marrow-derived cells. Comparable to our results, infiltration of the lungs with eosinophils and neutrophils was similar in mice with or without Arg1 ablation in hematopoietic cells.…”

mentioning

confidence: 99%

Ablation of Arg1 in hematopoietic cells improves respiratory function of lung parenchyma, but not that of larger airways or inflammation in asthmatic mice

Cloots

Sankaranarayanan

Theije

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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Cloots RH, Sankaranarayanan S, de Theije CC, Poynter ME, Terwindt E, van Dijk P, Hakvoort TB, Lamers WH, Köhler SE. Ablation of Arg1 in hematopoietic cells improves respiratory function of lung parenchyma, but not that of larger airways or inflammation in asthmatic mice. Am J Physiol Lung Cell Mol Physiol 305: L364-L376, 2013. First published July 5, 2013; doi:10.1152/ajplung.00341.2012.-Asthma is a chronic inflammatory disease of the small airways, with airway hyperresponsiveness (AHR) and inflammation as hallmarks. Recent studies suggest a role for arginase in asthma pathogenesis, possibly because arginine is the substrate for both arginase and NO synthase and because NO modulates bronchial tone and inflammation. Our objective was to investigate the importance of increased pulmonary arginase 1 expression on methacholine-induced AHR and lung inflammation in a mouse model of allergic asthma. Arginase 1 expression in the lung was ablated by crossing Arg1 fl/fl with Tie2Cre tg/Ϫ mice. Mice were sensitized and then challenged with ovalbumin. Lung function was measured with the Flexivent. Adaptive changes in gene expression, chemokine and cytokine secretion, and lung histology were quantified with quantitative PCR, ELISA, and immunohistochemistry. Arg1 deficiency did not affect the allergic response in lungs and large-airway resistance, but it improved peripheral lung function (tissue elastance and resistance) and attenuated adaptive increases in mRNA expression of arginine-catabolizing enzymes Arg2 and Nos2, arginine transporters Slc7a1 and Slc7a7, chemokines Ccl2 and Ccl11, cytokines Tnfa and Ifng, mucus-associated epithelial markers Clca3 and Muc5ac, and lung content of IL-13 and CCL11. However, expression of Il4, Il5, Il10, and Il13 mRNA; lung content of IL-4, IL-5, IL-10, TNF-␣, and IFN-␥ protein; and lung pathology were not affected. Correlation analysis showed that Arg1 ablation disturbed the coordinated pulmonary response to ovalbumin challenges, suggesting arginine (metabolite) dependence of this response. Arg1 ablation in the lung improved peripheral lung function and affected arginine metabolism but had little effect on airway inflammation. airway hyperresponsiveness; arginine; inflammation ALLERGIC ASTHMA IS A CHRONIC inflammatory disorder of the lung that is characterized by a reversible limitation of the airflow due to an allergic reaction in the airways with the characteristics of a T H 2-predominant airway inflammation. The airway inflammation is initiated by the binding of inhaled allergens to complementary IgEs on IgE receptor-bearing cells. Upon activation, these cells release histamine, cytokines, and proteases, resulting in the activation of the inflammatory cascade with lung infiltration of eosinophils and mononuclear cells. Increased mucus production, mucosal edema, and a disproportionate smooth-muscle contraction lead to airway hyperresponsiveness (AHR). As a result of the recurring inflammation, airway remodeling develops as a consequence of fibrosis and airway wall thickening (2,3,6,36).Rec...

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Bone marrow cell derived arginase I is the major source of allergen-induced lung arginase but is not required for airway hyperresponsiveness, remodeling and lung inflammatory responses in mice

Abstract: Background: Arginase is significantly upregulated in the lungs in murine models of asthma, as well as in human asthma, but its role in allergic airway inflammation has not been fully elucidated in mice.

Cited by 25 publications

References 55 publications

Increased arginase activity contributes to airway remodelling in chronic allergic asthma

Increased arginase activity contributes to airway remodelling in chronic allergic asthma

Resistin-Like Molecule–α Regulates IL-13–Induced Chemokine Production but Not Allergen-Induced Airway Responses

Ablation of Arg1 in hematopoietic cells improves respiratory function of lung parenchyma, but not that of larger airways or inflammation in asthmatic mice

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