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MyD88: A central mediator of corneal...

Johnson, Angela Christine.

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MyD88: A central mediator of corneal epithelial innate immune responses.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	MyD88: A central mediator of corneal epithelial innate immune responses./
Author:	Johnson, Angela Christine.
Description:	160 p.
Notes:	Adviser: Eric Pearlman.
Contained By:	Dissertation Abstracts International68-09B.
Subject:	Biology, Cell. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3285348
ISBN:	9780549258780

MyD88: A central mediator of corneal epithelial innate immune responses.
Johnson, Angela Christine.

MyD88: A central mediator of corneal epithelial innate immune responses. - 160 p.

Adviser: Eric Pearlman.

Thesis (Ph.D.)--Case Western Reserve University, 2008.

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 Pam3Cys 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-kappaB 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.

ISBN: 9780549258780Subjects--Topical Terms:

1017686
Biology, Cell.

MyD88: A central mediator of corneal epithelial innate immune responses.
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100 1 $a Johnson, Angela Christine. $3 1279955
245 1 0 $a MyD88: A central mediator of corneal epithelial innate immune responses.
300 $a 160 p.
500 $a Adviser: Eric Pearlman.
500 $a Source: Dissertation Abstracts International, Volume: 68-09, Section: B, page: 5738.
502 $a Thesis (Ph.D.)--Case Western Reserve University, 2008.
520 $a 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 Pam3Cys 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-kappaB 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.
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