NADPH Oxidase has a Regulatory Role in Acute Allergic Asthma


  • Ena Ray Banerjee Department of Zoology, University of Calcutta, 35 Ballygunge Circular Road, Kolkata-700019, West Bengal, India.
  • William R. Henderson Jr. Department of Medicine, Division of Allergy and Infectious Diseases, Center for Allergy and Inflammation, University of Washington, Room 254, 815 Mercer Street, Seattle, WA 98195, USA.


NADPH Oxidase, gp91phox-/- mouse, OVA-specific IgE, T cell, Allergic Asthma, BALf, Wildtype and Knockout mice


Objective: For the establishment of inflammation, a constant interplay between different effector cells from circulation, local resident cells, soluble mediators and genetic host factors is required. Molecular mechanisms, initiating and perpetuating inflammation, in particular, the involvement of effector cells in redox reactions for producing O2- (superoxide anion) through the mediation of NADPH oxidase is a critical step. Prior data suggest that reactive oxygen species (ROS) produced by NADPH oxidase homologues in non-phagocytic cells play an important role in the regulation of signal transduction, while macrophages use a membrane-associated NADPH oxidase to generate an array of oxidizing intermediates which inactivate MMPs on or near them.

Materials, Methods and Treatment: To clarify the role of NADPH oxidase in T cell-initiated, macrophage-associated allergic asthma, we induced allergen dependent inflammation in a gp91phox-/- mouse.

Results: Both inflammation and airway hyperreactivity were more extensive than in wildtype mice post-OVA. Although OVA-specific IgE in plasma were comparable in wildtype and knockout mice, enhanced inflammatory cell recruitment from circulation and cytokine release in lung and BALf, accompanied by higher airway resistance as well as Penh in response to methacholine, indicates a regulatory role for NADPH oxidase in development of allergic asthma. While T cell-mediated functions like Th2 cytokine secretion, and proliferation to OVA were up-regulated synchronous with the overall robustness of the asthma phenotype, macrophage up-regulation in functions such as proliferation, mixed lymphocyte reaction, and MCP-1 directed chemotaxis, but downregulation of respiratory burst response indicates a forking in their signaling pathways. gp91phox-/- MMP12 double knockout (DKO) mice show a similar phenotype as the gp91phox-/- showing the non-involvement or synergistic involvement of MMP12 in the response pathway. In mixed lymphocyte reaction using the Increased B7.1 but reduced B7.2 and MHC class II expression indicating alteration of co-stimulatory molecule expression critical for T cell activation on both gp91phox-/- and DKO mice may explain the mechanism by which gp91phox may regulate Th2 pathway in allergic asthma.


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[1]. Groemping, Y., and Rittinger, K. (2005). Activation and assembly of the NADPH oxidase: a structural perspective. Biochem. J., 386: 401–416.
[2]. Henriet, S.S., Hermans, P.W., Verweij, P.E., Simonetti, E., Holland, S.M., Sugui, J.A., Kwon-Chung, K.J., Warris, A. (2010). Human leukocytes kill Aspergillus nidulans by ROS-independent mechanisms. Infect. Immun., 79(2):767-73.
[3]. Bylund, J., Brown, K.L., Movitz, C., Dahlgren, C., Karlsson, A. (2010). Intracellular generation of superoxide by the phagocyte NADPH oxidase: How, where, and what for? Free Radic. Biol. Med., 49(12):1834-45.
[4]. Kumar, S., Patel, S., Jyoti, A., Keshari, R.S., Verma, A., Barthwal, M.K., Dikshit, M. (2010). Nitric oxide-mediated augmentation of neutrophil reactive oxygen and nitrogen species formation: Critical use of probes. Cytometry A., 77(11):1038-48.
[5]. De Ravin, S.S., Zarember, K.A., Long-Priel, D., Chan, K.C., Fox, S.D., Gallin, J.I., Kuhns, D.B., Malech, H.L. (2010). Tryptophan/kynurenine metabolism in human leukocytes is independent of superoxide and is fully maintained in chronic granulomatous disease. Blood, 116(10):1755-60.
[6]. Chan, E.C., Dusting, G.J., Guo, N., Peshavariya, H.M., Taylor, C.J., Dilley, R., Narumiya, S., Jiang, F. (2010). Prostacyclin receptor suppresses cardiac fibrosis: role of CREB phosphorylation. J. Mol. Cell. Cardiol., 49(2):176-85.
[7]. Leverence, J.T., Medhora, M., Konduri, G.G., Sampath, V. (2010). Lipopolysaccharide-induced cytokine expression in alveolar epithelial cells: Role of PKC?-mediated p47phox phosphorylation. Chem. Biol. Interact., 189(1-2):72-81.
[8]. Kim, Y., Zhou, M., Moy, S., Morales, J., Cunningham, M.A., Joachimiak, A. (2010). High-resolution structure of the nitrile reductase QueF combined with molecular simulations provide insight into enzyme mechanism. J. Mol. Biol., 404(1):127-37.
[9]. Santilli, G., Almarza, E., Brendel, C., Choi, U., Beilin, C., Blundell, M.P., Haria, S., Parsley, K.L., Kinnon, C., Malech, H.L., Bueren, J.A., Grez, M., Thrasher, A.J. (2010). Biochemical Correction of X-CGD by a Novel Chimeric Promoter Regulating High Levels of Transgene Expression in Myeloid Cells. Mol. Ther., 19(1):122-32.
[10]. Kassim, S.Y., Fu, X., Liles, W.C., Shapiro, S.D., Parks, W.C., Heinecke, J.W. (2005). NADPH oxidase restrains the matrix metalloproteinase activity of macrophages. J. Biol. Chem., 280(34):30201-5.
[11]. Pollock, J.D., Williams, D.A., Gifford, M.A., Li, L.L., Du, X., Fisherman, J., Orkin, S.H., Doerschuk, C.M., Dinauer, M.C. (1995). Mouse model of X-linked chronic granulomatous disease, an inherited defect in phagocyte superoxide production. Nat. Genet., 9, 202-9.
[12]. Shipley, J.M., Wesselschmidt, R.L., Kobayashi, D.K., Ley, T.J., Shapiro, S.D. (1996). Metalloelastase is required for macrophage-mediated proteolysis and matrix invasion in mice. Proc. Natl. Acad. Sci. U. S. A., 93: 3942–3946.
[13]. Ena Ray Banerjee, Yi Jiang, William R. Henderson, Jr, Yvette Latchman, and Thalia Papayannopoulou (2009). Absence of ?4 but not ?2 integrins restrains the development of chronic allergic asthma using mouse genetic models. Exp. Hematol., 37: 715–727.
[14]. Ena R. Banerjee, Yvette E. Latchman, Yi Jiang, Greg V. Priestley, and Thalia Papayannopoulou (2008). Distinct changes in adult lymphopoiesis in Rag2-/- mice fully reconstituted by ?4-deficient adult bone marrow cells. Exp. Hematol., 36(8):1004-13.
[15]. Ulyanova, T., Priestley, G.V., Banerjee, E.R., Papayannopoulou, T. (2007). Unique and redundant roles of alpha4 and beta2 integrins in kinetics of recruitment of lymphoid vs myeloid cell subsets to the inflamed peritoneum revealed by studies of genetically deficient mice. Exp. hematol., 35(8): 1256-65.
[16]. Banerjee, E.R., Jiang, Y., Henderson, W.R. Jr, Scott, L.M., Papayannopoulou, T. (2007). Alpha4 and beta2 integrins have nonredundant roles in asthma development, but for optimal allergen sensitization only alpha4 is critical. Exp. Hematol., 35(4): 605-17.
[17]. William, R., Henderson, Ena Ray Banerjee, and Emil Y. Chi (2005). Differential Effects of (S)- and (R)-enantiomers of albuterol in mouse asthma Model. Journal of Allergy and Clinical Immunology, 116: 332-40.
[18]. Sophie Lanone, Tao Zheng, Zhou Zhu, Wei Liu, Chun Geun Lee, Bing Ma, Qingsheng Chen, Robert J. Homer, Jingming Wang, Lesley A. Rabach, Morgan E. Rabach, J. Michael Shipley, Steven D. Shapiro, Robert M. Senior, and Jack A. Elias (2002). Overlapping and enzyme-specific contributions of matrix metalloproteinases-9 and -12 in IL-13–induced inflammation and remodeling. J. Clin. Invest., 110(4):463–474.
[19]. Roza, I. Nurieva, Xoi Moui Mai, Katherine Forbush, Michael J. Bevan and Chen Dong (2003). B7h is required for T cell activation, differentiation, and effector function. PNAS, 100: 14163-14168.
[20]. Shengdian Wang., Gefeng Zhu., Andrei I., Chapoval., Haidong Dong., Koji Tamada., Jian Ni and LiepingChe (2000). Costimulation of T cells by B7-H2, a B7-like molecule that binds ICOS. Blood, Vol. 96, No. 8, pp. 2808-281.
[21]. Suh, W.K., Tafuri, A., Berg-Brown, N.N., Shahinian, A., Plyte, S., Duncan, G.S., Okada, H., Wakeham, A., Odermatt, B., Ohashi, P., Mak, T.W. (2004). The inducible costimulator plays the major costimulatory role in humoral immune responses in the absence of CD28. J. Immunol., 172(10):5917- 23.
[22]. Hutloff, A., Dittrich, A.M., Beier, K.C., Eljaschewitsch, B., Kraft, R., Anagnostopoulos, I., Kroczek, R.A. (1999). ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28. Nature, 397(6716):263-6.
[23]. Yoshinaga, S.K. Whoriskey, J.S., Khare, S.D., Sarmiento, U., Guo, J., Horan, T., Shih, G. et al., (1999). T-cell co-stimulation through B7RP-1 and ICOS. Nature, 402(6763):827-32.
[24]. Qian, X., Agematsu, K., Freeman, G.J., Tagawa, Y., Sugane, K., Hayashi, T. (2006). The ICOS-ligand B7-H2, expressed on human type II alveolar epithelial cells, plays a role in the pulmonary host defense system. Eur. J. Immunol., 36(4):906-18.
[25]. M. Schuyler., K. Gott and B. Edwards (1999). Th1 Cells That Adoptively Transfer Experimental Hypersensitivity Pneumonitis Are Activated Memory Cells. Lung, 177(6): 377-89.
[26]. Gudmundsson, G., Hunninghake, G.W. (1997). Interferon-gamma is necessary for the expression of hypersensitivity pneumonitis. J. Clin. Invest., 99:2386-2390.
[27]. Gunnar Gudmundsson, Martha M. Monick and Gary W. Hunninghake (1998). IL-12 Modulates Expression of Hypersensitivity Pneumonitis. J. Immunol., 161(2):991-9.
[28]. Boyd G.C., McSharry, K., McLeod, S., Sriram, and F. Boyd (1999). Lymphocyte responses in pigeon breeders with extrinsic allergic alveolitis/hypersensitivity pneumonitis (EAA/HP) are predominantly T helper 2-type. Am. J. Respir. Crit. Care Med., 159:A742.
[29]. Meyer, F., Ramanujam, K.S., Gobert, A.P., James, S.P. and Wilson, K.T. (2003). Cyclooxygenase-2 activation suppresses Th1 polarization in response to Helicobacter pylori. J. Immunol., 171:3913-7.
[30]. Lenschow, D.J., T.L. Walunas., J.A. Bluestone. (1996). CD28/B7 system of T cell costimulation. Annu. Rev. Immunol., 14:233-58.
[31]. Linsley, P.S., P.M. Wallace., J. Johnson., M.G. Gibson., J.L. Greene., J.A. Ledbetter., C. Singh., M.A. Tepper (1992). Immunosuppression in vivo by a soluble form of the CTLA-4 T cell activation molecule. Science, 257:792-5.
[32]. Thompson, C.B. (1995). Distinct roles for the costimulatory ligands B7-1 and B7-2 in T helper cell differentiation? Cell, 81(7):979-82.
[33]. Schweitzer, A.N., Sharpe, A.H. (1998). Studies using antigen-presenting cells lacking expression of both B7-1 (CD80) and B7-2 (CD86) show distinct requirements for B7 molecules during priming versus restimulation of Th2 but not Th1 cytokine production. J. Immunol., 161:2762-2771.
[34]. Chelen, C.J., Fang, Y., Freeman, G.J., Secrist, H., Marshall, J.D., Hwang, P.T., Frankel, L.R., DeKruyff, R.H., Umetsu, D.T. (1995). Human alveolar macrophages present antigen ineffectively due to defective expression of B7 costimulatory cell surface molecules. J. Clin. Invest., 95(3):1415-21.




How to Cite

Banerjee, E. R., & Henderson Jr., W. R. (2011). NADPH Oxidase has a Regulatory Role in Acute Allergic Asthma. Journal of Advanced Laboratory Research in Biology, 2(3), 79–97. Retrieved from