Pollen is a ubiquitous allergen that affects a large population with allergic diseases. However, the mechanisms leading to resolution of pollen allergen-induced inflammation remain poorly understood, a knowledge gap preventing us from developing new targeted therapies to cure allergic diseases. We have recently uncovered a novel pollen/TLR4 innate immunity pathway where short ragweed (SRW) pollen triggers allergic inflammation via TLR4-dependent innate signaling by mucosal epithelium that produces proallergic cytokine thymic stromal lymphopoietin (TSLP). We thus extended our investigation to another epithelial proallergic cytokine interleukine (IL) 33 and other major innate immune cells that may respond to pollen allergen. We hypothesize that TLR4-dependent innate immunity by ocular mucosal epithelia, dendritic cells and macrophages in response to pollen allergen, initiates Th2-dominant allergic inflammation via two stimulated allergic pathways, TSLP/OX40L/OX40 and IL-33/ST2, with an inhibited protective signaling IL-27/IL-10. The long-term goal of this project is to discover new molecular mechanisms and novel therapeutic targets for treating allergic diseases.
Four Specific Aims are proposed to fulfill this novel project for public health.
Aim 1 is to confirm the hypothesis that SRW pollen stimulates production of two pro-allergic cytokines TSLP and IL-33 by ocular epithelium via activating TLR4/MyD88/NF-?B innate immunity pathway;
Aim 2 is to investigate the hypothesis that TLR4-dependent innate immune responses by dendritic cells amplify Th2-dominant inflammation via autocrine activation of TSLP/OX40L and IL-33/ST2 signaling with inhibitory regulation of IL-27 in response to SRW pollen allergen;
Aim 3 is to explore the hypothesis that SRW pollen allergen primes macrophage polarization toward an alternatively activated (M2) phenotype to promote Th2- inducing cytokines (TSLP, IL-33 and OX40L) and Th2-attracting chemokines (CCL17 and CCL22) via TLR4-dependent innate immunity;
and Aim 4 is to test the hypothesis that pollen/TLR4 concept may create a novel TLR4-targeted therapy for pollen-triggered allergic diseases using TLR4 antagonists and/or agonists. At the conclusion of this project, we will uncover a novel phenomenon and molecular mechanism by which pollen allergen triggers Th2-dominant allergic inflammation via TLR4-dependent innate immune response that activates TSLP/OX40L/OX40 and IL-33/ST2 allergic pathways but suppresses IL-27/IL-10 protective signaling in mucosal innate immunity system. The end product of this project will be a fundamental new understanding and potential TLR4-targeted therapeutic strategies, a new hope to prevent and cure allergic disease.

Public Health Relevance

This is a clinically relevant translational basic research proposal. This project will uncover a novel mechanism, a pollen/TLR4 concept, by which pollen allergen triggers allergic inflammation via TLR4-dependent innate immunity pathway that activates proallergic signaling TSLP and IL-33 while inhibits protective signaling IL-27/IL-10 in mucosal epithelia, dendritic cells and/or macrophages. When accomplished, this project will develop a fundamental new understanding and targeted therapeutic strategies, which open a hope to cure allergic disease.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY023598-04
Application #
9303347
Study Section
Diseases and Pathophysiology of the Visual System Study Section (DPVS)
Program Officer
Mckie, George Ann
Project Start
2014-08-01
Project End
2019-07-31
Budget Start
2017-08-01
Budget End
2018-07-31
Support Year
4
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Li, Jin; Xiao, Yangyan; Coursey, Terry G et al. (2017) Identification for Differential Localization of Putative Corneal Epithelial Stem Cells in Mouse and Human. Sci Rep 7:5169
Chen, D; Qu, Y; Hua, X et al. (2017) A hyaluronan hydrogel scaffold-based xeno-free culture system for ex vivo expansion of human corneal epithelial stem cells. Eye (Lond) 31:962-971
Chi, Wei; Hua, Xia; Chen, Xin et al. (2017) Mitochondrial DNA oxidation induces imbalanced activity of NLRP3/NLRP6 inflammasomes by activation of caspase-8 and BRCC36 in dry eye. J Autoimmun 80:65-76
Li, Jin; Zhang, Lili; Chen, Xin et al. (2016) Pollen/TLR4 Innate Immunity Signaling Initiates IL-33/ST2/Th2 Pathways in Allergic Inflammation. Sci Rep 6:36150
Li, Jin; Ruzhi Deng; Hua, Xia et al. (2016) Blueberry Component Pterostilbene Protects Corneal Epithelial Cells from Inflammation via Anti-oxidative Pathway. Sci Rep 6:19408
Hua, Xia; Su, Zhitao; Deng, Ruzhi et al. (2015) Effects of L-carnitine, erythritol and betaine on pro-inflammatory markers in primary human corneal epithelial cells exposed to hyperosmotic stress. Curr Eye Res 40:657-67
Hua, Xia; Deng, Ruzhi; Li, Jin et al. (2015) Protective Effects of L-Carnitine Against Oxidative Injury by Hyperosmolarity in Human Corneal Epithelial Cells. Invest Ophthalmol Vis Sci 56:5503-11
Qu, Yangluowa; Chi, Wei; Hua, Xia et al. (2015) Unique expression pattern and functional role of periostin in human limbal stem cells. PLoS One 10:e0117139
Hua, Xia; Yuan, Xiaoyong; Li, Zhijie et al. (2015) A Novel Innate Response of Human Corneal Epithelium to Heat-killed Candida albicans by Producing Peptidoglycan Recognition Proteins. PLoS One 10:e0128039
Deng, Ruzhi; Hua, Xia; Li, Jin et al. (2015) Oxidative stress markers induced by hyperosmolarity in primary human corneal epithelial cells. PLoS One 10:e0126561

Showing the most recent 10 out of 11 publications