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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Ferguson, Stacy E
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Los Angeles
Schools of Medicine
Los Angeles
United States
Zip Code
Boxx, Gayle M; Cheng, Genhong (2016) The Roles of Type I Interferon in Bacterial Infection. Cell Host Microbe 19:760-9
Qin, F Xiao-Feng; Jiang, Cheng-Yu; Jiang, Taijiao et al. (2015) New targets for controlling Ebola virus disease. Natl Sci Rev 2:266-267
Ma, Feng; Li, Bing; Liu, Su-yang et al. (2015) Positive feedback regulation of type I IFN production by the IFN-inducible DNA sensor cGAS. J Immunol 194:1545-54
Ma, Feng; Liu, Su-Yang; Razani, Bahram et al. (2014) Retinoid X receptor α attenuates host antiviral response by suppressing type I interferon. Nat Commun 5:5494
Teles, Rosane M B; Graeber, Thomas G; Krutzik, Stephan R et al. (2013) Type I interferon suppresses type II interferon-triggered human anti-mycobacterial responses. Science 339:1448-53
Wang, Yaya; Shaked, Iftach; Stanford, Stephanie M et al. (2013) The autoimmunity-associated gene PTPN22 potentiates toll-like receptor-driven, type 1 interferon-dependent immunity. Immunity 39:111-22
Wilson, Elizabeth B; Yamada, Douglas H; Elsaesser, Heidi et al. (2013) Blockade of chronic type I interferon signaling to control persistent LCMV infection. Science 340:202-7
Kamo, Naoko; Ke, Bibo; Ghaffari, Amir A et al. (2013) ASC/caspase-1/IL-1β signaling triggers inflammatory responses by promoting HMGB1 induction in liver ischemia/reperfusion injury. Hepatology 58:351-62
Iyer, Shankar Subramanian; Cheng, Gehong (2012) Role of interleukin 10 transcriptional regulation in inflammation and autoimmune disease. Crit Rev Immunol 32:23-63
Liu, Su-Yang; Sanchez, David Jesse; Aliyari, Roghiyh et al. (2012) Systematic identification of type I and type II interferon-induced antiviral factors. Proc Natl Acad Sci U S A 109:4239-44

Showing the most recent 10 out of 48 publications