The long term goal of this application is to further elucidate the Toll-Like Receptor (TLR)-mediated signaling and gene expression network (gene program) in regulating Th17 cell differentiation and its associated autoimmune diseases. Upon recognizing pathogen-associated molecular patterns or host danger signals, host pattern recognition receptors such as the TLRs can initiate a series of signal transduction and gene expression cascades for host defense against invading pathogens and other stresses. The signaling specificity of individual TLRs, initiated through differential recruitment of adaptor molecules such as MyD88 and TRIF, can be further amplified by differential induction of cytokines, which are not only important for innate immune responses but also play critical roles in instructing the directions of adaptive immune responses, including different types of T-cells. Th17 cells are a subtype of CD4+T helper cells believed to be important for host defense against pathogen infections, whereas elevated Th17 responses can lead to many autoimmune and inflammatory diseases such as multiple sclerosis in human and its similar disease in mouse, Experimental Autoimmune Encephalomyelitis (EAE). Recent studies have identified IL-1, IL-6, TGF2, and IL-23 as the promoters and IL-27 and IL-10 as the suppressors for the differentiation of Th17 cells. However, the mechanisms responsible for regulating these cytokines during in vivo immune responses are still not fully understood. Our recent studies have shown that while MyD88-deficient mice failed to develop EAE, mice lacking either TRIF or type I interferon (IFN) receptor (IFNAR) have elevated Th17 cells in the central nervous system and develop much more severe EAE than wild type mice. We hypothesize that TRIF-mediated type I IFN induction plays critical roles in suppressing Th17-associated autoimmune and inflammatory diseases such as EAE. Based on our preliminary studies, we further hypothesize that the IFN2-mediated inhibition of Th17 cell differentiation through IL-27 induction as the mechanism by which IFN2 can successfully treat human multiple sclerosis. The goal of this proposal is to understand the mechanisms by which TLR-mediated gene programs regulate Th17 cell differentiation and modulate Th17-associated autoimmune and inflammatory diseases through activation of the type I interferon pathway. We will first define which TLR mediates MyD88- dependent pathways in promoting EAE and which TLR mediates TRIF-dependent pathways in suppressing EAE. We will also determine the contributions and the mechanisms of IL-27 induction in type I IFN-mediated negative regulation of Th17 differentiation. Finally, we will explore the possibilities of modulating this TRIF and IFN1/2-dependent gene program to treat Th17-mediated inflammatory diseases. Our proposed studies will not only elucidate the physiological role of endogenous type I IFNs in inhibiting the development of autoimmune disease, but will also provide insight to understand how IFN2 works in the treatment of Multiple Sclerosis and to help design additional strategies to treat autoimmune and inflammatory disease.

Public Health Relevance

Although type I interferon (IFN), especially IFN2, has been successfully used to treat autoimmune diseases such as multiple sclerosis, the molecular mechanism behind such a treatment is not known. Our recent studies suggest that type I IFN can effectively suppress multiple sclerosis through inhibiting a type of inflammatory immune cells called Th17 cells. The goal of our research is to further elucidate the molecular mechanisms responsible for IFN mediated anti-inflammatory responses and discover novel therapeutic targets for treating different types of autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI056154-08
Application #
8260282
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Ferguson, Stacy E
Project Start
2003-07-01
Project End
2015-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
8
Fiscal Year
2012
Total Cost
$370,138
Indirect Cost
$122,638
Name
University of California Los Angeles
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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