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MYD88: A CENTRAL MEDIATOR OF CORNEAL EPITHELIAL INNATE IMMUNE RESPONSES

Johnson, Angela Christine
http://rave.ohiolink.edu/etdc/view?acc_num=case1192559051

Abstract Details

2008, Doctor of Philosophy, Case Western Reserve University, Pathology.
Toll-like Receptors (TLRs) are innate immune receptors that recognize both bacterial and viral pathogens. As the cornea may become infected by these pathogens, leading to vision loss, initial studies addressed the functional presence of TLRs within this tissue, thereby yielding a model of how immunological responses are initiated within the cornea. It has been determined that TLR2 and TLR9 are functionally necessary for the generation of inflammatory responses, as genetically deficient mice were impaired in their ability to respond to Pam 3Cys and unmethylated CpG DNA, respectively. MyD88 is a common adaptor molecule that is utilized by all TLRs, except TLR3. Consistent with this notion, it was shown that MyD88 is critical for the generation of TLR2, TLR4, and TLR9-induced keratitis, as defined by the production of CXC chemokines, neutrophil migration, and clinical disease (stromal haze and thickness). Taken together, these data indicate that MyD88 plays a critical role in positively mediating corneal inflammation. In order to assess the necessity of MyD88-independent, TRIF-dependent inflammation, studies were performed with TLR3 -/-and TRIF -/-mice and demonstrated that TLR3/TRIF is necessary for the development of corneal inflammation in response to Poly(I:C). Surprisingly, inflammation was significantly increased in MyD88 -/-mice, as measured by macrophage and neutrophil infiltration and corneal disease (stromal haze); and, therefore, we have unveiled a novel function of MyD88, in that it negatively regulates TLR3/TRIF induced inflammation. Additionally, human corneal epithelial cells are subject to the negative regulation imposed by MyD88. Furthermore, it was demonstrated that TLR3/TRIF dependent JNK, but not p38, IRF-3, or NF-κB signaling, is negatively regulated by MyD88; therefore, MyD88-dependent negative inhibition controls JNK signaling after TLR3/TRIF activation. Taken together, we propose that MyD88 functions to positively mediate (TLR2, TLR4, and TLR9) and negatively regulate (TLR3) corneal inflammation. Further understanding into the novel regulatory pathway by which MyD88 controls TLR3/TRIF activation will lead to the development of more rational treatment strategies, as data presented here indicates that MyD88 depletion would be beneficial for bacterial keratitis, but increased levels of MyD88 protein would be helpful for the treatment of viral keratitis.
Eric Pearlman (Advisor)
corneal epithelium; innate immunity; Toll-like receptor; signaling pathways

Recommended Citations

Citations

  • Johnson, A. C. (2008). MYD88: A CENTRAL MEDIATOR OF CORNEAL EPITHELIAL INNATE IMMUNE RESPONSES [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1192559051

    APA Style (7th edition)

  • Johnson, Angela. MYD88: A CENTRAL MEDIATOR OF CORNEAL EPITHELIAL INNATE IMMUNE RESPONSES. 2008. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1192559051.

    MLA Style (8th edition)

  • Johnson, Angela. "MYD88: A CENTRAL MEDIATOR OF CORNEAL EPITHELIAL INNATE IMMUNE RESPONSES." Doctoral dissertation, Case Western Reserve University, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=case1192559051

    Chicago Manual of Style (17th edition)

case1192559051
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© 2007, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.