Inflammatory bowel diseases (IBDs) including Crohn's disease (CD) and ulcerative colitis (UC) are chronic diseases characterized by a pronounced infiltration of neutrophils (PMNs) into colonic mucosal lesions, accompanied by epithelial cell necrosis and ulceration. Disease activity and patient symptoms also correlate with the histologic finding of PMN infiltrates within the mucosa and surface epithelium. This same histological event of massive transepithelial migration of PMNs occurs in the acute phase of gastroenteritis induced by Salmonella enterica serovar Typhimurium (salmonellosis). Thus, insight into pathogen elicited active inflammation of the intestine will serve as an important model to provide valuable information relating to active inflammation in IBD. Using the enteric pathogen S. typhimurium as a tool to investigate mechanisms underlying PMN recruitment across the intestinal epithelia, we have demonstrated a novel and central role for the eicosanoid hepoxilin A3 (HXA3). HXA3 is a derivative of arachidonic acid formed from the enzymatic action of the 12-lipoxygenase (12-LO) pathway. This observation has unlocked a previous unexplored phenomenon that mechanistically explains a primary histopathologic feature of active states of intestinal inflammation. Moreover, we have recently shown that HXA3 is secreted through an efflux transport system located at the apical surface of the intestinal epithelia that involves the ABC transporter MRP2. We also revealed that induction of intestinal inflammation corresponds to a profound up-regulation of the apical expression of MRP2. Such up-regulation of MRP2 was further demonstrated in vivo in chronic murine models of IBD and human intestinal biopsy tissues from patients with active CD or UC. Thus, the primary objectives of this project are to understand the molecular mechanisms underlying HXA3 synthesis (Specific Aim 1), as well as to determine how HXA3 production is regulated (Specific Aim 2). To accomplish these aims we plan to use a combination of complementary in vitro and in vivo models coupled with state of the art cellular, molecular, and biochemical techniques. We hypothesize that understanding HXA3/MRP2 based signaling, which directs the movement of PMNs across the intestinal epithelium, will lead to the development of important therapeutics designed to help control this inflammatory event in patients with infectious, allergic, and idiopathic (IBD) colitis.
It is estimated that as many as one million Americans have inflammatory bowel disease (IBD) with that number evenly split between Crohn's disease and ulcerative colitis. Males and females appear to be affected equally. IBDs including Crohn's disease and ulcerative colitis are chronic recurrent inflammatory disorders of the gastrointestinal tract that are of unkown etiology. Although the exact pathogenesis of IBDs is poorly understood, evidence indicates that it involves interaction between the immune system, genetic susceptibility, and the environment. These diseases are characterized by a pronounced infiltration of neutrophils (PMNs) into colon mucosal lesions, accompanied by epithelial cell necrosis and ulceration. Moreover, disease activity and patient symptoms correlate with the histologic finding of PMN infiltrates within the mucosa and surface epithelium. Curiously, this same histological event of massive transepithelial migration of PMNs occurs in the acute phase of gastroenteritis induced by Salmonella enteritis serovar Typhimurium (salmonellosis). Thus, while the evolution of these responses most likely initially targeted pathogens such as S. typhimurium, perhaps aberrant activation of such pathways also occurs, leading to inappropriate states of active intestinal inflammation. The goal of this proposal is to understand the molecular mechanisms by which S. typhimurium triggers and controls the directed movement of PMN across the epithelial surface so that novel targets for therapeutic intervention in such inflammatory bowel diseases can be identified.
|Bhowmick, Rudra; Clark, Stacie; Bonventre, Joseph V et al. (2017) Cytosolic Phospholipase A2? Promotes Pulmonary Inflammation and Systemic Disease during Streptococcus pneumoniae Infection. Infect Immun 85:|
|Hallstrom, Kelly N; McCormick, Beth A (2016) The type three secreted effector SipC regulates the trafficking of PERP during Salmonella infection. Gut Microbes 7:136-45|
|Saslowsky, David E; Thiagarajah, Jay R; McCormick, Beth A et al. (2016) Microbial sphingomyelinase induces RhoA-mediated reorganization of the apical brush border membrane and is protective against invasion. Mol Biol Cell 27:1120-30|
|Mercado-Lubo, Regino; Zhang, Yuanwei; Zhao, Liang et al. (2016) A Salmonella nanoparticle mimic overcomes multidrug resistance in tumours. Nat Commun 7:12225|
|Hallstrom, Kelly N; Srikanth, C V; Agbor, Terence A et al. (2015) PERP, a host tetraspanning membrane protein, is required for Salmonella-induced inflammation. Cell Microbiol 17:843-59|
|Wall, Daniel M; McCormick, Beth A (2014) Bacterial secreted effectors and caspase-3 interactions. Cell Microbiol 16:1746-56|
|Agbor, Terence A; Demma, Zachary; Mrsny, Randall J et al. (2014) The oxido-reductase enzyme glutathione peroxidase 4 (GPX4) governs Salmonella Typhimurium-induced neutrophil transepithelial migration. Cell Microbiol 16:1339-53|
|Mallick, Emily M; Garber, John J; Vanguri, Vijay K et al. (2014) The ability of an attaching and effacing pathogen to trigger localized actin assembly contributes to virulence by promoting mucosal attachment. Cell Microbiol 16:1405-24|
|Liu, Zongcai; Meng, Fanwei; Li, Chan et al. (2014) Human umbilical cord mesenchymal stromal cells rescue mice from acetaminophen-induced acute liver failure. Cytotherapy 16:1207-19|
|Jandhyala, Dakshina M; Vanguri, Vijay; Boll, Erik J et al. (2013) Shiga toxin-producing Escherichia coli O104:H4: an emerging pathogen with enhanced virulence. Infect Dis Clin North Am 27:631-49|
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