Requirement for Chemokine Receptor 5 in the Development of Allergen-Induced Airway Hyperresponsiveness and Inflammation

Published on Jul 14, 2011in American Journal of Respiratory Cell and Molecular Biology5.373
· DOI :10.1165/RCMB.2010-0465OC
Yasuko Fuchimoto9
Estimated H-index: 9
(Okayama University),
Arihiko Kanehiro25
Estimated H-index: 25
+ 8 AuthorsMitsune Tanimoto68
Estimated H-index: 68
Sources
Abstract
Chemokine receptor (CCR) 5 is expressed on dendritic cells, macrophages, CD8 cells, memory CD4 T cells, and stromal cells, and is frequently used as a marker of T helper type 1 cells. Interventions that abrogate CCR5 or interfere with its ligand binding have been shown to alter T helper type 2–induced inflammatory responses. The role of CCR5 on allergic airway responses is not defined. CCR5-deficient (CCR5−/−) and wild-type (CCR5+/+) mice were sensitized and challenged with ovalbumin (OVA) and allergic airway responses were monitored 48 hours after the last OVA challenge. Cytokine levels in lung cell culture supernatants were also assessed. CCR5−/− mice showed significantly lower airway hyperresponsiveness (AHR) and lower numbers of total cells, eosinophils, and lymphocytes in bronchoalveolar lavage (BAL) fluid compared with CCR5+/+ mice after sensitization and challenge. The levels of IL-4 and IL-13 in BAL fluid of CCR5−/− mice were lower than in CCR5+/+ mice. Decreased numbers of lung T cells were also detected in CCR5−/− mice after sensitization and challenge. Transfer of OVA-sensitized T cells from CCR5+/+, but not transfer of CCR5−/− cells, into CCR5−/− mice restored AHR and numbers of eosinophils in BAL fluid after OVA challenge. Accordingly, the numbers of airway-infiltrating donor T cells were significantly higher in the recipients of CCR5+/+ T cells. Taken together, these data suggest that CCR5 plays a pivotal role in allergen-induced AHR and airway inflammation, and that CCR5 expression on T cells is essential to the accumulation of these cells in the airways.
📖 Papers frequently viewed together
47 Citations
75 Citations
247 Citations
References37
Newest
#1Nobuaki MiyaharaH-Index: 33
#2Hiroshi Ohnishi (University of Colorado Denver)H-Index: 20
Last. Erwin W. Gelfand (University of Colorado Denver)H-Index: 113
view all 12 authors...
Previous studies have shown that leukotriene B4 (LTB4), a proinflammatory lipid mediator, is linked to the development of airway hyperresponsiveness through the accumulation of IL-13–producing CD8+ T cells, which express a high affinity receptor for LTB4, BLT1 (Miyahara et al., Am J Respir Crit Care Med 2005;172:161–167; J Immunol 2005;174:4979–4984). By using leukotriene A4 hydrolase–deficient (LTA4H−/−) mice, which fail to synthesize LTB4, we determined the role of this lipid mediator in aller...
39 CitationsSource
#1Nobuaki MiyaharaH-Index: 33
#2Hiroshi OhnishiH-Index: 20
Last. Erwin W. GelfandH-Index: 113
view all 11 authors...
Dendritic cells (DC) are important APCs that control allergen-induced airway responses by interacting directly with T cells. Leukotriene B4 (LTB4), interacting with its high-affinity receptor, LTB4 receptor 1 (BLT1), is known to attract and activate leukocytes during inflammation. We have previously shown that BLT1 expression on Ag-primed T cells is required for the development of airway hyperresponsiveness (AHR; Miyahara et al. 2005. Am. J. Respir. Crit. Care Med. 172: 161–167). However, the ro...
48 CitationsSource
#1Yasue Suzaki (Nara Medical University)H-Index: 8
#2Kaoru HamadaH-Index: 24
Last. Hiroshi KimuraH-Index: 50
view all 8 authors...
Asthma is associated with increased numbers of T-cells in the lung. CC chemokine receptor (CCR)5 and CXC chemokine receptor (CXCR)3 have been reported to play important roles in the lung T-cell homing pathway, and may be potential targets for asthma therapy. The aim of the present study was to investigate the role of CCR5 and CXCR3 in allergen-induced acute asthma and to determine whether a novel small-molecule compound, TAK-779, targeting CCR5 and CXCR3 can attenuate allergic airway responses. ...
45 CitationsSource
#1Shipra Gupta (MHH: Hannover Medical School)H-Index: 4
#2Barbara Fuchs (Fraunhofer Society)H-Index: 10
Last. Ulf Forssmann (MHH: Hannover Medical School)H-Index: 17
view all 11 authors...
Modulation of leukocyte recruitment through intervention with chemokine receptors is an attractive, therapeutic strategy. Recently, we have shown that n-Nonanoyl (NNY)-CCL14 internalizes and desensitizes human (h)CCR3, resulting in the inactivation of eosinophils. In this study, we investigated the interaction of NNY-CCL14 with CCR1 and CCR5 and the relevance of these NNY-CCL14 receptors on its in vivo effects in allergic airway inflammation. NNY-CCL14 has inactivating properties on CCR1 + and C...
8 CitationsSource
#1Young Mok LeeH-Index: 21
#2Nobuaki MiyaharaH-Index: 33
Last. Azzeddine Dakhama (National Jewish Health)H-Index: 6
view all 9 authors...
Rationale: Severe respiratory syncytial virus (RSV) bronchiolitis has been associated with deficient IFN-γ production in humans, but the role of this cytokine in determining the outcome of reinfection is unknown. Objectives: To define the role of IFN-γ in the development of RSV-mediated airway hyperresponsiveness (AHR) and lung histopathology in mice. Methods: Wild-type (WT) and IFN-γ knockout mice were infected with RSV in the newborn or weaning stages and reinfected 5 weeks later. Airway respo...
68 CitationsSource
#1Hiroshi OhnishiH-Index: 20
#2Nobuaki Miyahara (Okayama University)H-Index: 33
Last. Erwin W. GelfandH-Index: 113
view all 3 authors...
ABSTRACT Leukotriene B 4 (LTB 4 ) is a lipid mediator with potent chemoattractant properties and that is rapidly generated from activated innate immune cells such as neutrophils, macrophages, and mast cells. Elevated levels of LTB 4 have been reported in various allergic diseases and these levels have been related to disease activity and response to treatment. Recent studies using LTB 4 receptor-1 (BLT1) antagonists or BLT1-deficient mice have revealed that ligation of BLT1 by LTB 4 is important...
94 CitationsSource
#1Lander Robays (Ghent University Hospital)H-Index: 5
#2Tania Maes (Ghent University Hospital)H-Index: 32
Last. Karim V. Vermaelen (Ghent University Hospital)H-Index: 1
view all 8 authors...
Increased numbers of pulmonary dendritic cells (DCs) are recruited to the lungs during allergic airway inflammation and contribute to the maintenance of the inflammatory immune response. The chemokine receptors that directly control DC accumulation into the lungs are largely unknown. To explore this issue, we generated mixed bone marrow chimeric mice containing both wild-type and knockout cells for a given chemokine receptor. After induction of allergic airway inflammation, we specifically track...
114 CitationsSource
#1Atsushi Hirano (Okayama University)H-Index: 8
#2Arihiko Kanehiro (Okayama University)H-Index: 25
Last. Mitsune TanimotoH-Index: 68
view all 11 authors...
We investigated the therapeutic potential of a newly developed antifibrotic agent, pirfenidone, to regulate airway remodeling and the development of allergic airway inflammation and airway hyperresponsiveness after chronic allergen challenge. Administration of pirfenidone after sensitization but during the period of ovalbumin challenge significantly prevented the development of airway hyperresponsiveness and prevented eosinophil and lymphocyte accumulation in the airways. IL-4, IL-5, and IL-13 l...
53 CitationsSource
RANTES (CC chemokine ligand 5) contributes to airway inflammation through accumulation of eosinophils, but the exact role of RANTES (CCL5) is not defined. C57BL/6 mice, sensitized by injection of ovalbumin (OVA) on Days 1 and 14, were challenged with OVA on Days 28, 29, and 30 (3 challenges, short-term–challenge model) or on Days 28, 29, 30, 36, 40, 44, and 48 (7 challenges, repeated–challenge model) and evaluated 48 h later. Anti-mouse RANTES was given intravenously, and recombinant mouse RANTE...
19 CitationsSource
#1Christian TaubeH-Index: 51
#2Nobuaki MiyaharaH-Index: 33
Last. Erwin W. GelfandH-Index: 113
view all 11 authors...
Studies in both humans and rodents have suggested that CD8+ T cells contribute to the development of airway hyperresponsiveness (AHR) and that leukotriene B4 (LTB4) is involved in the chemotaxis of effector CD8+ T cells (TEFF) to the lung by virtue of their expression of BLT1, the receptor for LTB4. In the present study, we used a mast cell-CD8-dependent model of AHR to further define the role of BLT1 in CD8+ T cell-mediated AHR. C57BL/6+/+ and CD8-deficient (CD8−/−) mice were passively sensitiz...
92 CitationsSource
Cited By14
Newest
#1Marc GauthierH-Index: 7
#2Sagar Laxman KaleH-Index: 7
Last. Prabir Ray (University of Pittsburgh)H-Index: 55
view all 12 authors...
BACKGROUND Many severe asthma (SA) patients fail to respond to Type 2 inflammation targeted therapies. We previously identified a cohort of SA subjects expressing Type 1 inflammation manifesting with IFN-γ expression with variable Type 2 responses. OBJECTIVE We investigated the role of the chemotactic receptors CXCR3 and CCR5 in establishing Type 1 inflammation in SA. METHODS Bronchoalveolar lavage microarray data from the Severe Asthma Research Program (SARP I/II) were analyzed for pathway expr...
Source
#1Yingli Zhang (SYSU: Sun Yat-sen University)H-Index: 2
#2Rongrong Liang (SYSU: Sun Yat-sen University)H-Index: 1
Last. Yingqiang Zhong (SYSU: Sun Yat-sen University)H-Index: 2
view all 6 authors...
Asthma is a heterogeneous chronic inflammatory disorder of the airways with a complex etiology, which involves a variety of cells and cellular components. Therefore, the aim of the study was to investigate the effects and mechanisms of antagonistic peptides that specifically bind to the first and second extracellular loops of CCR5 (GH and HY peptides, respectively) and anti-interleukin-23 subunit p19 (anti-IL-23p19) in the airway and thereby mediate inflammation and the IL-23/T helper 17 (Th17) ...
1 CitationsSource
#1Kazuyuki Nakagome (Saitama Medical University)H-Index: 11
#2Makoto Nagata (Saitama Medical University)H-Index: 20
Eosinophilic pneumonia (EP), including acute EP and chronic EP, is characterized by the massive pulmonary infiltration of eosinophils into the lung. However, the mechanisms underlying the selective accumulation of eosinophils in EP have not yet been fully elucidated. We reported that bronchoalveolar lavage fluid (BALF) from EP patients induced the transmigration of eosinophils across endothelial cells in vitro. The concentrations of eotaxin-2 (CCL24) and monocyte chemotactic protein (MCP)-4 (CCL...
3 CitationsSource
#1Yoshiki Kobayashi (Kansai Medical University)H-Index: 15
#2Yasunori Konno (Akita University)H-Index: 11
Last. Shigeharu Ueki (Akita University)H-Index: 22
view all 10 authors...
BACKGROUND: Excessive eosinophil airway infiltration is a clinically critical condition in some cases. Eosinophilic pneumonia (EP) is a pulmonary condition involving eosinophil infiltration of the lungs. Although several chemokines, including eotaxin-1 (CCL11), RANTES (CCL5) and macrophage inflammatory protein 1β (MIP-1β or CCL4), have been detected in bronchoalveolar lavage fluid (BALF) from patients with EP, the pathophysiological mechanisms underlying EP, including potential relationships bet...
12 CitationsSource
#1Ming‑Wei Liu (Kunming Medical University)H-Index: 5
#1Ming‑Wei Liu (Kunming Medical University)H-Index: 5
Last. Mei‑Xian Su (Kunming Medical University)H-Index: 5
view all 15 authors...
Airway remodeling in asthma contributes to airway hyperreactivity, loss of lung function and persistent symptoms. Current therapies do not adequately treat the structural airway changes associated with asthma. Statin drugs have improved respiratory health and their therapeutic potential in asthma has been tested in clinical trials. However, the mechanism of action of statins in this context has remained elusive. The present study hypothesized that atorvastatin treatment of ovalbumin-exposed mice...
8 CitationsSource
#1Utako Fujii (Okayama University)H-Index: 6
#2Nobuaki Miyahara (Okayama University)H-Index: 33
Last. Arihiko Kanehiro (Okayama University)H-Index: 25
view all 12 authors...
Background Retinoid X receptors (RXRs) are members of the nuclear receptor (NR) superfamily that mediate signaling by 9-cis retinoic acid, a vitamin A (retinol) derivative. RXRs play key roles not only as homodimers but also as heterodimeric partners—e.g., retinoic acid receptors (RARs), vitamin D receptors (VDRs), liver X receptors (LXRs), and peroxisome proliferator-activated receptors (PPARs). The NR family was recently associated with allergic diseases, but the role of RXRs in allergen-induc...
14 CitationsSource
#1Utako FujiiH-Index: 6
#2Nobuaki Miyahara (Okayama University)H-Index: 33
Last. Arihiko KanehiroH-Index: 25
view all 13 authors...
We recently reported that IL-17A plays a critical role in the development of porcine pancreatic elastase (PPE)–induced emphysema. The proliferation of T-helper type 17 (Th17) cells was induced by IL-23. To determine the contribution of IL-23 to the development of pulmonary emphysema, a mouse model of PPE-induced emphysema was used in which responses of IL-23p19–deficient (IL-23−/−) and wild-type (WT) mice were compared. Intratracheal instillation of PPE induced emphysematous changes in the lungs...
11 CitationsSource
#1Akihiko Taniguchi (Okayama University)H-Index: 10
#2Nobuaki Miyahara (RMIT: RMIT University)H-Index: 33
Last. Arihiko Kanehiro (Okayama University)H-Index: 25
view all 12 authors...
The receptor for advanced glycation end-products (RAGE) is a multiligand receptor that belongs to the immunoglobulin superfamily. RAGE is reported to be involved in various inflammatory disorders; however, studies that address the role of RAGE in allergic airway disease are inconclusive. RAGE-sufficient (RAGE+/+) and RAGE-deficient (RAGE−/−) mice were sensitized to ovalbumin, and airway responses were monitored after ovalbumin challenge. RAGE−/− mice showed reduced eosinophilic inflammation and ...
15 CitationsSource
#1Koichi Waseda (Okayama University)H-Index: 9
#2Nobuaki Miyahara (RMIT: RMIT University)H-Index: 33
Last. Arihiko KanehiroH-Index: 25
view all 12 authors...
Pulmonary emphysema is characterized by persistent inflammation and progressive alveolar destruction. The receptor for advanced glycation end-products (RAGE) is a multiligand cell surface receptor reported to be involved in the process of acute alveolar epithelial cell injury. However, studies that address the role of RAGE in pulmonary emphysema are inconclusive. We investigated the role of RAGE in the development of elastase-induced pulmonary inflammation and emphysema in mice. RAGE-sufficient ...
16 CitationsSource
The respiratory tract and lungs are part of a complex organ system, the cardiorespiratory system, designed to facilitate the exchange of gases, such as oxygen and carbon dioxide, maintain acid–base and electrolyte imbalance, and serve as an important mechanism for filtering potentially harmful environmental materials. Respirable-size particulate matter, from environmental or industrial exposure, can induce the expression of inflammatory mediators in various cell types of the lung. Previous studi...
Source