Role of thymic stromal lymphopoietin in chronic rhinosinusitis Abstract: The overall goal of the studies in this project is to test the hypothesis hat Th2-related inflammatory responses in polypoid chronic rhinosinusitis are mediated, in part, by expression of the cytokine thymic stromal lymphopoietin (TSLP) in sinus tissue. Chronic rhinosinusitis (CRS) is a heterogeneous disease characterized by local inflammation of the upper airways and sinuses that is unresponsive to antibiotic therapy and which persists for at least 12 weeks. It is one of the most common chronic diseases in adults in the United States, affecting over 20 million Americans, and has a severe impact on patients'quality of life and healthcare costs. CRS is most commonly treated with antibiotics, steroids, and allergy medications. Due to poor responses to medical therapy, over 250,000 surgical procedures are performed annually in the United States. Therefore it is necessary that we better understand the pathogenic mechanisms of this disease in order to generate novel medical treatments. CRS is clinically classified into CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP). Both forms are characterized by intense inflammatory cell infiltration which drives symptoms of the disease, but CRSwNP is the more severe form of the two and is characterized by Th2-related inflammation including eosinophilia. However, the regulation of Th2 inflammation in CRSwNP is still largely unknown. In this proposal we will focus on TSLP, a cytokine that is recognized as a master regulator of Th2 inflammation. We have exciting evidence that TSLP is highly up-regulated in nasal polyps from patients with CRSwNP and high levels of TSLP are significantly correlated with eosinophilia and expression of Th2 cytokines in nasal polyps. In addition, we have found that nasal polyp extracts can truncate TSLP, and the truncated products may have more potent activity than the full-length form. We therefore hypothesize that TSLP and its truncated products play an important pathogenic role in CRSwNP. We propose experiments to test this hypothesis using in vitro and in vivo approaches. We are compelled to test this hypothesis in humans because TSLP has species-specific activities and there is no animal model of CRS. Studies in Aim 1 will test the hypothesis that the family of serine proteases plays an important role in the posttranslational modification of TSLP in NPs. Studies in Aim 2 will test the hypothesis that posttranslational modification of TSLP by NP proteases results in higher TSLP activity than the full-length form. Studies in Aim 3 will test the hypothesi that TSLP and truncated TSLP play an important role in Th2-related inflammation in NPs. We believe that the proposed studies will reveal whether TSLP and truncated TSLP are potential targets for medical treatment of CRS.

Public Health Relevance

Chronic rhinosinusitis is a disease that affects over 20 million Americans in whom it causes considerable morbidity and leads to over 250,000 surgeries per year. We have discovered that the cytokine TSLP is up- regulated in patients with polypoid chronic rhinosinusitis and levels of TSLP are significantly correlated with tissue Th2-related inflammation. The studies in this grant will test our hypothesis that the over production of TSLP and its truncated products contribute to the initiation and activation of polypoid chronic rhinosinusitis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI104733-01A1
Application #
8691135
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Minnicozzi, Michael
Project Start
2014-02-15
Project End
2019-01-31
Budget Start
2014-02-15
Budget End
2015-01-31
Support Year
1
Fiscal Year
2014
Total Cost
$386,250
Indirect Cost
$136,250
Name
Northwestern University Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Tan, Bruce K; Klingler, Aiko I; Poposki, Julie A et al. (2016) Heterogeneous inflammatory patterns in chronic rhinosinusitis without nasal polyps in Chicago, Illinois. J Allergy Clin Immunol :
Stevens, Whitney W; Schleimer, Robert P (2016) Aspirin-Exacerbated Respiratory Disease as an Endotype of Chronic Rhinosinusitis. Immunol Allergy Clin North Am 36:669-680
Min, Jin-Young; Ocampo, Christopher J; Stevens, Whitney W et al. (2016) Proton pump inhibitors decrease eotaxin-3/CCL26 expression in patients with chronic rhinosinusitis with nasal polyps: Possible role of the nongastric H,K-ATPase. J Allergy Clin Immunol :
Poposki, Julie A; Keswani, Anjeni; Kim, Julie K et al. (2016) Tissue proteases convert CCL23 into potent monocyte chemoattractants in patients with chronic rhinosinusitis. J Allergy Clin Immunol 137:1274-1277.e9
Homma, Tetsuya; Kato, Atsushi; Bhushan, Bharat et al. (2016) Role of Aspergillus fumigatus in Triggering Protease-Activated Receptor-2 in Airway Epithelial Cells and Skewing the Cells toward a T-helper 2 Bias. Am J Respir Cell Mol Biol 54:60-70
Poposki, Julie A; Klingler, Aiko I; Stevens, Whitney W et al. (2016) Proprotein convertases generate a highly functional heterodimeric form of thymic stromal lymphopoietin in humans. J Allergy Clin Immunol :
Stevens, Whitney W; Ocampo, Christopher J; Berdnikovs, Sergejs et al. (2015) Cytokines in Chronic Rhinosinusitis. Role in Eosinophilia and Aspirin-exacerbated Respiratory Disease. Am J Respir Crit Care Med 192:682-94
Kato, Atsushi (2015) Immunopathology of chronic rhinosinusitis. Allergol Int 64:121-30
Poposki, J A; Peterson, S; Welch, K et al. (2015) Elevated presence of myeloid dendritic cells in nasal polyps of patients with chronic rhinosinusitis. Clin Exp Allergy 45:384-93
Seshadri, Sudarshan; Lu, Xiang; Purkey, Matthew R et al. (2015) Increased expression of the epithelial anion transporter pendrin/SLC26A4 in nasal polyps of patients with chronic rhinosinusitis. J Allergy Clin Immunol 136:1548-58.e1-7

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