Attenuation of antigen-induced airway hyperresponsiveness and inflammation in CXCR3 knockout mice

Respiratory Research

Jinming Gao²  Bao Lu³  Wexun Zhou⁶  Zijian Guo²  Kewu Huang⁴  Huaxia Chen²  Lei Jiang²  Ruolan Xiang⁵  Hongmei Piao¹  Yu Xiao⁶  Haibo Yan¹  Yi Lin² 

[1] Department of Respiratory Diseases, Yanbian University Affiliated Hospital, Yanbian, Jilin 133000, China;Department of Respiratory Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China;Ina Sue Perlmutter Laboratory, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA;Department of Respiratory Medicine, Chaoyang Hospital, Capital University of Medical Sciences, Beijing 100023, China;Department of Physiology and Pathophysiology, Peking University Health Sciences Center, Beijing 100088, China;Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China

关键词: airway hyperresponsiveness;    airway inflammation;    CD8+ T lymphocyte;    CXCR3;    chemokine receptor;   

Others  :  796799
DOI  :  10.1186/1465-9921-12-123

 received in 2011-05-04, accepted in 2011-09-22,  发布年份 2011

【 摘 要 】

Background

CD8+ T cells participate in airway hyperresponsiveness (AHR) and allergic pulmonary inflammation that are characteristics of asthma. CXCL10 by binding to CXCR3 expressed preferentially on activated CD8+ T cells, attracts T cells homing to the lung. We studied the contribution and limitation of CXCR3 to AHR and airway inflammation induced by ovalbumin (OVA) using CXCR3 knockout (KO) mice.

Methods

Mice were sensitized and challenged with OVA. Lung histopathological changes, AHR, cellular composition and levels of inflammatory mediators in bronchoalveolar lavage (BAL) fluid, and lungs at mRNA and protein levels, were compared between CXCR3 KO mice and wild type (WT) mice.

Results

Compared with the WT controls, CXCR3 KO mice showed less OVA-induced infiltration of inflammatory cells around airways and vessels, and less mucus production. CXCR3 KO mice failed to develop significant AHR. They also demonstrated significantly fewer CD8+ T and CD4+ T cells in BAL fluid, lower levels of TNFα and IL-4 in lung tissue measured by real-time RT-PCR and in BAL fluid by ELISA, with significant elevation of IFNγ mRNA and protein expression levels.

Conclusions

We conclude that CXCR3 is crucial for AHR and airway inflammation by promoting recruitment of more CD8+ T cells, as well as CD4+ T cells, and initiating release of proinflammatory mediators following OVA sensitization and challenge. CXCR3 may represent a novel therapeutic target for asthma.

【 授权许可】

   
2011 Lin et al; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Bateman ED, Hurd SS, Barnes PJ, Bousquet J, Drazen JM, FitzGerald M, Gibson P, Ohta K, O'Byrne P, Pedersen SE, et al.: Global strategy for asthma management and prevention: Gina executive summary. Eur Respir J 2008, 31(1):143-178.
• [2]Holgate ST, Polosa R: The mechanisms, diagnosis, and management of severe asthma in adults. Lancet 2006, 368(9537):780-793.
• [3]Chanez P, Wenzel SE, Anderson GP, Anto JM, Bel EH, Boulet LP, Brightling CE, Busse WW, Castro M, Dahlen B, et al.: Severe asthma in adults: What are the important questions? J Allergy Clin Immunol 2007, 119(6):1337-1348.
• [4]Brightling C, Berry M, Amrani Y: Targeting tnf-alpha: A novel therapeutic approach for asthma. J Allergy Clin Immunol 2008, 121(1):5-10. quiz 11-12
• [5]Barnes PJ: The cytokine network in asthma and chronic obstructive pulmonary disease. J Clin Invest 2008, 118(11):3546-3556.
• [6]D'Ambrosio D, Panina-Bordignon P, Sinigaglia F: Chemokine receptors in inflammation: An overview. J Immunol Methods 2003, 273(1-2):3-13.
• [7]D'Ambrosio D, Mariani M, Panina-Bordignon P, Sinigaglia F: Chemokines and their receptors guiding t lymphocyte recruitment in lung inflammation. Am J Respir Crit Care Med 2001, 164(7):1266-1275.
• [8]Loetscher M, Gerber B, Loetscher P, Jones SA, Piali L, Clark-Lewis I, Baggiolini M, Moser B: Chemokine receptor specific for ip10 and mig: Structure, function, and expression in activated t-lymphocytes. J Exp Med 1996, 184(3):963-969.
• [9]Jinquan T, Jing C, Jacobi HH, Reimert CM, Millner A, Quan S, Hansen JB, Dissing S, Malling HJ, Skov PS, et al.: Cxcr3 expression and activation of eosinophils: Role of ifn-gamma-inducible protein-10 and monokine induced by ifn-gamma. J Immunol 2000, 165(3):1548-1556.
• [10]Liu LY, Jarjour NN, Busse WW, Kelly EA: Chemokine receptor expression on human eosinophils from peripheral blood and bronchoalveolar lavage fluid after segmental antigen challenge. The Journal of allergy and clinical immunology 2003, 112(3):556-562.
• [11]Medoff BD, Sauty A, Tager AM, Maclean JA, Smith RN, Mathew A, Dufour JH, Luster AD: Ifn-gamma-inducible protein 10 (cxcl10) contributes to airway hyperreactivity and airway inflammation in a mouse model of asthma. J Immunol 2002, 168(10):5278-5286.
• [12]Kurashima K, Fujimura M, Myou S, Ishiura Y, Onai N, Matsushima K: Asthma severity is associated with an increase in both blood cxcr3+ and ccr4+ t cells. Respirology (Carlton, Vic 2006, 11(2):152-157.
• [13]Kurashima K, Fujimura M, Myou S, Kasahara K, Tachibana H, Amemiya N, Ishiura Y, Onai N, Matsushima K, Nakao S: Effects of oral steroids on blood cxcr3+ and ccr4+ t cells in patients with bronchial asthma. Am J Respir Crit Care Med 2001, 164(5):754-758.
• [14]Suzaki Y, Hamada K, Nomi T, Ito T, Sho M, Kai Y, Nakajima Y, Kimura H: A small-molecule compound targeting ccr5 and cxcr3 prevents airway hyperresponsiveness and inflammation. Eur Respir J 2008, 31(4):783-789.
• [15]Hancock WW, Lu B, Gao W, Csizmadia V, Faia K, King JA, Smiley ST, Ling M, Gerard NP, Gerard C: Requirement of the chemokine receptor cxcr3 for acute allograft rejection. The Journal of experimental medicine 2000, 192(10):1515-1520.
• [16]Nie L, Xiang R, Zhou W, Lu B, Cheng D, Gao J: Attenuation of acute lung inflammation induced by cigarette smoke in cxcr3 knockout mice. Respir Res 2008, 9:82. BioMed Central Full Text
• [17]Nie L, Xiang RL, Liu Y, Zhou WX, Jiang L, Lu B, Pang BS, Cheng DY, Gao JM: Acute pulmonary inflammation is inhibited in cxcr3 knockout mice after short-term cigarette smoke exposure. Acta pharmacologica Sinica 2008, 29(12):1432-1439.
• [18]Nie L, Liu ZJ, Zhou WX, Xiang RL, Xiao Y, Lu B, Pang BS, Gao JM: Chemokine receptor cxcr3 is important for lung tissue damage and airway remodeling induced by short-term exposure to cigarette smoking in mice. Acta Pharmacol Sin 31(4):436-442.
• [19]Medoff BD, Okamoto Y, Leyton P, Weng M, Sandall BP, Raher MJ, Kihara S, Bloch KD, Libby P, Luster AD: Adiponectin deficiency increases allergic airway inflammation and pulmonary vascular remodeling. Am J Respir Cell Mol Biol 2009, 41(4):397-406.
• [20]Wittke A, Weaver V, Mahon BD, August A, Cantorna MT: Vitamin d receptor-deficient mice fail to develop experimental allergic asthma. J Immunol 2004, 173(5):3432-3436.
• [21]Thomas SY, Banerji A, Medoff BD, Lilly CM, Luster AD: Multiple chemokine receptors, including ccr6 and cxcr3, regulate antigen-induced t cell homing to the human asthmatic airway. J Immunol 2007, 179(3):1901-1912.
• [22]Campbell JD, Gangur V, Simons FE, HayGlass KT: Allergic humans are hyporesponsive to a cxcr3 ligand-mediated th1 immunity-promoting loop. Faseb J 2004, 18(2):329-331.
• [23]Betts RJ, Kemeny DM: Cd8+ t cells in asthma: Friend or foe? Pharmacol Ther 2009, 121(2):123-131.
• [24]Gelfand EW, Dakhama A: Cd8+ t lymphocytes and leukotriene b4: Novel interactions in the persistence and progression of asthma. J Allergy Clin Immunol 2006, 117(3):577-582.
• [25]Miyahara N, Swanson BJ, Takeda K, Taube C, Miyahara S, Kodama T, Dakhama A, Ott VL, Gelfand EW: Effector cd8+ t cells mediate inflammation and airway hyper-responsiveness. Nat Med 2004, 10(8):865-869.
• [26]Koya T, Miyahara N, Takeda K, Matsubara S, Matsuda H, Swasey C, Balhorn A, Dakhama A, Gelfand EW: Cd8+ t cell-mediated airway hyperresponsiveness and inflammation is dependent on cd4+il-4+ t cells. J Immunol 2007, 179(5):2787-2796.
• [27]Schwarze J, Cieslewicz G, Joetham A, Ikemura T, Hamelmann E, Gelfand EW: Cd8 t cells are essential in the development of respiratory syncytial virus-induced lung eosinophilia and airway hyperresponsiveness. J Immunol 1999, 162(7):4207-4211.
• [28]Doherty TA, Soroosh P, Broide DH, Croft M: Cd4+ cells are required for chronic eosinophilic lung inflammation but not airway remodeling. American journal of physiology 2009, 296(2):L229-235.
• [29]Gavett SH, Chen X, Finkelman F, Wills-Karp M: Depletion of murine cd4+ t lymphocytes prevents antigen-induced airway hyperreactivity and pulmonary eosinophilia. American journal of respiratory cell and molecular biology 1994, 10(6):587-593.
• [30]Schwarze J, Cieslewicz G, Joetham A, Ikemura T, Makela MJ, Dakhama A, Shultz LD, Lamers MC, Gelfand EW: Critical roles for interleukin-4 and interleukin-5 during respiratory syncytial virus infection in the development of airway hyperresponsiveness after airway sensitization. Am J Respir Crit Care Med 2000, 162(2 Pt 1):380-386.
• [31]Cho SH, Stanciu LA, Holgate ST, Johnston SL: Increased interleukin-4, interleukin-5, and interferon-gamma in airway cd4+ and cd8+ t cells in atopic asthma. Am J Respir Crit Care Med 2005, 171(3):224-230.
• [32]Wills-Karp M: Interleukin-13 in asthma pathogenesis. Immunol Rev 2004, 202:175-190.
• [33]Lack G, Renz H, Saloga J, Bradley KL, Loader J, Leung DY, Larsen G, Gelfand EW: Nebulized but not parenteral ifn-gamma decreases ige production and normalizes airways function in a murine model of allergen sensitization. J Immunol 1994, 152(5):2546-2554.
• [34]Lack G, Bradley KL, Hamelmann E, Renz H, Loader J, Leung DY, Larsen G, Gelfand EW: Nebulized ifn-gamma inhibits the development of secondary allergic responses in mice. J Immunol 1996, 157(4):1432-1439.
• [35]Koya T, Takeda K, Kodama T, Miyahara N, Matsubara S, Balhorn A, Joetham A, Dakhama A, Gelfand EW: Rantes (ccl5) regulates airway responsiveness after repeated allergen challenge. Am J Respir Cell Mol Biol 2006, 35(2):147-154.
• [36]Dow SW, Schwarze J, Heath TD, Potter TA, Gelfand EW: Systemic and local interferon gamma gene delivery to the lungs for treatment of allergen-induced airway hyperresponsiveness in mice. Hum Gene Ther 1999, 10(12):1905-1914.
• [37]Mikhak Z, Fukui M, Farsidjani A, Medoff BD, Tager AM, Luster AD: Contribution of ccr4 and ccr8 to antigen-specific t(h)2 cell trafficking in allergic pulmonary inflammation. J Allergy Clin Immunol 2009, 123(1):67-73 e63.
• [38]Barnes PJ: New therapies for asthma: Is there any progress? Trends Pharmacol Sci 31(7):335-343.