Project 4 (Sur, S)
Sanjiv Sur, MD
Professor in Internal Medicine
Department of Internal Medicine-Allergy
301 University Blvd.
Galveston, TX 77555-1083
Dr. Sur's bio...
Exposure to pollens is one of the most common causes of respiratory allergies such as allergic rhinitis and allergic asthma worldwide. We have previously shown that pollens contain an enzyme called NADPH oxidase (pollen-NOX) and that this enzyme is critical for induction of allergic inflammation. However very little is known about the molecular mechanism by which these oxidases induce allergic diseases. Our goal in this proposal is to address this critical gap in knowledge about how pollen-NOX induces allergic inflammation.
The airway epithelium is the first line of defense against the harmful effects of pollens. Epithelial and intraepithelial dendritic (DCs) cells are two types of cells in the airway epithelium that are the key first responder cells to inhaled pollen allergens. We propose that one of the earliest events that happens when pollens land on the airway epithelium is that pollen-NOX binds to a receptor on the surface of DCs called Toll Receptor-4, TLR4. This cell surface receptor is best known for its ability to bind to a bacterial product called lipopolysaccharide or LPS, but its ability to bind pollen-NOX has not been described. Our hypothesis is that binding of pollen-NOX to TLR4 initiates oxidative stress in the DCs that is sufficiently severe to damage DNA, the cells genetic material (Fig. 1). This damaged DNA is repaired by DNA repair enzyme called OGG1, and 8-oxoG- the damaged base in the DNA, is released. OGG1 and 8-oxoG then form a signaling complex in DCs called OGG1-guanine nucleotide exchange factor, or OGG1GEF. This OGG1GEF induces a signaling cascade that activates DCs and promotes allergic inflammation.
Our proposed model of RWPNOX-induced signaling is shown above. Binding of RWPNOX to TLR4 ectodomain induces iROS that oxidatively damage mitochondria; they now also produce and amplify iROS. This oxidative stress induces DNA damage, and initiates OGG1-dependent DNA repair, thereby releasing free 8-oxoG base from the genome. The 8-oxoG binds to OGG1, forming OGG1GEF that activates MAPK and RelA to induce co-stimulatory molecules, and activate T cells. This signaling pathway does not require MyD88 or TRIF because it is initiated by ROS from RWPNOXWe will test our hypothesis in three Aims.
Achieving these Aims should identify novel molecular pathways utilized by pollen NADPH oxidases to activate DCs and induce allergic inflammation in humans. Our long-term goal is to develop inhibitors of these novel pathways and test their ability to prevent the allergic inflammation in patients suffering from allergic rhinitis and allergic asthma. These new treatments could decrease morbidity and mortality from these diseases.
- In Aim 1 we will test the hypothesis that RWPNOX induces iROS and DNA damage by binding to the ectodomain of TLR4.
- In Aim 2 we will test the hypothesis that RWPNOX-induced DNA-BER activates MAPK and RelA in DCs, and augments Ag-induced allergic airway inflammation.
- In Aim 3 we will test the hypothesis that interaction of RWPNOX with TLR4 initiates DNA-BER-mediated signaling pathways that upregulate co-stimulatory molecules and induce allergic inflammation in humans.
- Csillag, A., Boldogh, I.,Pazmandi, K., Magyarics, Z., Rajnavolgyi, E., S. Sur, Bacsi, A. Pollen grain-induced oxidative stress influences both innate and adaptive responses via altering dendritic cell function. J Immunol. 184(5):2377-85, 2010, PMID: 20118277, PMCID: PMC263823
- Aguilera-Aguirre L, Bacsi A, Saavedra-Molina A, Kurosky A, Sur S, Boldogh I. Mitochondrial dysfunction increases allergic airway inflammation. J Immunol. 2009 Oct 15;183(8):5379-87
- Goswami S, Angkasekwinai P, Shan M, Greenlee KJ, Barranco WT, Polikepahad S, Seryshev A, Song LZ, Redding D, Singh B, Sur S, Woodruff P, Dong C, Corry DB, Kheradmand F. Divergent functions for airway epithelial matrix metalloproteinase 7 and retinoic acid in experimental asthma. Nat Immunol. 2009, 10(5):496-503
- Dharajiya N, Vaidya SV, Murai H, Cardenas V, Kurosky A, Boldogh I, Sur S. FcgammaRIIb inhibits allergic lung inflammation in a murine model of allergic asthma. PLoS One 5(2):e9337, 2010. PMID: 20179765; PMCID: PMC2825267
- Csillag A, Boldogh I, Pazmandi K, Magyarics Z, Gogolak P, Sur S, Rajnavolgyi E, Bacsi A. Pollen-induced oxidative stress influences both innate and adaptive immune responses via altering dendritic cell functions. J Immunol. 2010 184(5):2377-85
- Murai, H., Choudhury, B, Qi, H., Wild, J. Dharajiya, N., Vaidya, S., Kalita, A., Bacsi, A, Corry, D., Kurosky, A, Brasier, A, Boldogh, I., and Sur, S. Alternaria-induced release of IL-18 from damaged airway epithelial cells: An NF-kB dependent mechanism of Th2 differentiation. PloS ONE, 2012;7(2):e30280 2012; PMID: 22347372; PMCID: PMC3274547
- Hajas G, Bacsi A, Aguilerra-Aguirre L, German P, Radak Z, Sur S, Hazra TK, Boldogh I. Biochemical identification of a hydroperoxide derivative of the free 8-oxo-7,8-dihydroguanine base. Free Radic Biol Med. 2012 52(4):749-56.
- Boldogh I, Hajas G, Aguilera-Aguirre L, Hegde ML, Radak Z, Bacsi A, Sur S, Hazra TK, Mitra S. Activation of ras signaling pathway by 8-oxoguanine DNA glycosylase bound to its excision product, 8-oxoguanine. J Biol Chem. 2012 287(25):20769-73.
- Hajas G, Bacsi A, Aguilera-Aguirre L, Hegde ML, Tapas KH, Sur S, Radak Z, Ba X, Boldogh I. 8-Oxoguanine DNA glycosylase-1 links DNA repair to cellular signaling via the activation of the small GTPase Rac1. Free Radic Biol Med. 2013 61C:384-394.
- Bacsi A, Aguilera-Aguirre L, Szczesny B, Radak Z, Hazra TK, Sur S, Ba X, Boldogh I. Down-regulation of 8-oxoguanine DNA glycosylase 1 expression in the airway epithelium ameliorates allergic lung inflammation. DNA Repair (Amst). 2013 12(1):18-26