Eosinophilic esophagitis (EoE) is a chronic immune system disease. It has been identified only in the past two decades, but is now considered a major cause of esophageal disorder in both pediatric and adult population. The current proposal is the extension of our studies that provided novel findings including the role of IL-15 responsive iNKT cells, significance of IL-18 in IL-15 induced esophageal eosinophilia, the chemoattractant role of nerve cells derived neuropeptide VIP in EoE, and most importantly we reported a critical role IL-18 to transform IL-5 generated nave eosinophils to CD274 expressed pathogenic eosinophils. The proposed extended studies will now establish the physiological role of IL-18 and VIP in eosinophils and mast cells accumulation and degranulation in and beyond the epithelial mucosa that promotes esophageal functional abnormalities including motility dysfunction in chronic EoE. The mechanisms driving the eosinophil and mast cell accumulation, activation and degranulation in the muscular mucosa is yet not fully understood. Notably, no evidence indicates that muscle or neuronal cells are the sources of eotaxin-1, -2 or -3. Even after a decade of reported highly induced eotaxin-3 and its correlation with esophageal eosinophilia, yet the direct physiological significance of eotaxin--3 is not established in EoE. Therefore, it is critical to understand the role of tissue specific IL-18 induction and the mechanisms operational in the trafficking and accumulation of IL-18 transformed pathogenic eosinophils and mast cells in and beyond the epithelial mucosa. Our reports indicates that eosinophils and mast cells accumulation promotes epithelial, subepithelial and muscular mucosa fibrosis, muscle cell hyperplasia and esophageal functional abnormalities in human EoE. Most recently, we reported that eosinophils accumulate adjacent to nerve cells and neuroendocrine cell-derived vasoactive intestinal peptide has a chemoattractant role for eosinophils similar to the eotaxin(s). In addition, most recently both in vitro and in vivo, we showed that VIP receptor antagonist restrict eosinophils motility. Therefore, our extended grant studies will test the hypotheses that IL-18 and a neuroendocrine cell-derived chemoattractant vasoactive intestinal peptide is critical for the maturation, activation, and accumulation of eosinophils and mast cells in each segment of the esophagus and are the key for the development of fibrosis associated strictures and motility dysfunction. Accordingly, we propose three specific aims to establish the mechanistic pathways involved in IL-18-driven eosinophil and mast cell maturation, activation, and degranulation in each segment of the esophageal mucosa (AIM I); tissue-specific IL-18 induction is critical in promoting EoE pathogenesis (AIM II) and lastly, establish the role of neuroendocrine cell-derived vasoactive intestinal peptide in eosinophil and mast cell accumulation and degranulation within the muscular mucosa that promote esophageal functional abnormalities including stricture development and motility dysfunction in EoE (Aim III).

Public Health Relevance

Eosinophilic esophagitis (EoE) is a chronic allergic disease of increasing prevalence and has approximate expenditure ranged from $500 million to $1.4 billion/year in the United States. Even after more than two decades of extensive research on EoE, still, the mechanism of eosinophils and mast cells maturation, activation, degranulation and accumulation in the in and muscular mucosa that promotes esophageal functional abnormalities is not understood. This extended grant proposal will establish the significance and interaction of IL-18 and nerve cells derived neuropeptide in eosinophils and mast cells-induced EoE pathogenesis, including esophageal functional abnormalities like, the development of stricture and motility dysfunction.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI080581-10
Application #
9836787
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Minnicozzi, Michael
Project Start
2009-07-22
Project End
2023-11-30
Budget Start
2019-12-01
Budget End
2020-11-30
Support Year
10
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Tulane University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
053785812
City
New Orleans
State
LA
Country
United States
Zip Code
70118
Mussarat, Ahad; Manohar, Murli; Verma, Alok K et al. (2018) Intestinal overexpression of interleukin (IL)-15 promotes tissue eosinophilia and goblet cell hyperplasia. Immunol Cell Biol 96:273-283
Sandersa, Nathan L; Venkateshaiah, Sathisha Upparahalli; Manohar, Murli et al. (2018) Interleukin-18 has an Important Role in Differentiation and Maturation of Mucosal Mast Cells. J Mucosal Immunol Res 2:
Venkateshaiah, Sathisha Upparahalli; Zhu, Xiang; Rajavelu, Priya et al. (2018) Regulatory effects of IL-15 on allergen-induced airway obstruction. J Allergy Clin Immunol 141:906-917.e6
Manohar, Murli; Verma, Alok K; Venkateshaiah, Sathisha Upparahalli et al. (2018) Role of eosinophils in the initiation and progression of pancreatitis pathogenesis. Am J Physiol Gastrointest Liver Physiol 314:G211-G222
Venkateshaiah, Sathisha Upparahalli; Mishra, Akanksha; Manohar, Murli et al. (2018) A critical role for IL-18 in transformation and maturation of naive eosinophils to pathogenic eosinophils. J Allergy Clin Immunol 142:301-305
Verma, Alok K; Manohar, Murli; Venkateshaiah, Sathisha Upparahalli et al. (2018) Role of Vasoactive Intestinal Peptide in Promoting the Pathogenesis of Eosinophilic Esophagitis (EoE). Cell Mol Gastroenterol Hepatol 5:99-100.e7
Manohar, Murli; Verma, Alok Kumar; Venkateshaiah, Sathisha Upparahalli et al. (2017) Pathogenic mechanisms of pancreatitis. World J Gastrointest Pharmacol Ther 8:10-25
Manohar, Murli; Verma, Alok K; Upparahalli Venkateshaiah, Sathisha et al. (2017) Food-Induced Acute Pancreatitis. Dig Dis Sci 62:3287-3297
Verma, Alok K; Manohar, Murli; Upparahalli Venkateshaiah, Sathisha et al. (2017) Neuroendocrine cells derived chemokine vasoactive intestinal polypeptide (VIP) in allergic diseases. Cytokine Growth Factor Rev 38:37-48
Manohar, Murli; Verma, Alok K; Venkateshaiah, Sathisha Upparahalli et al. (2017) Chronic Pancreatitis Associated Acute Respiratory Failure. MOJ Immunol 5:

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