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J. Biol. Chem., Vol. 283, Issue 7, 3988-3996, February 15, 2008

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MyD88 Functions as a Negative Regulator of TLR3/TRIF-induced Corneal Inflammation by Inhibiting Activation of c-Jun N-terminal Kinase^*

Angela C. Johnson, Xiaoxia Li, and Eric Pearlman, Recipient of a Research to Prevent Blindness Senior Investigator Award¹

From the Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio 44106 and the Department of Immunology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 44195

The adaptor molecule MyD88 is necessary for responses to all Toll-like receptors except TLR3 and a subset of TLR4 signaling events, which are mediated by the adaptor molecule TRIF. To determine the role of TRIF in host inflammatory responses, corneal epithelium of C57BL/6, TLR3^-/-, TRIF^-/-, and MyD88^-/- mice was abraded and stimulated with the synthetic TLR3 ligand poly(I:C). We found that poly(I:C) induced a pronounced cellular infiltration into the corneal stroma, which was TLR3- and TRIF-dependent. Unexpectedly, the inflammatory response was exacerbated in MyD88^-/- mice, with enhanced neutrophil and F4/80⁺ cell infiltration into the corneal stroma and elevated corneal haze, which is an indicator of loss of corneal transparency. To determine whether MyD88-dependent inhibition of TLR3/TRIF responses is a general phenomenon, we examined cytokine production by MyD88^-/- bone marrow-derived macrophages; however, no significant difference was observed between MyD88^+/+ or MyD88^-/- macrophages. Incontrast, human corneal epithelial cells (HCECs) transfected with MyD88 small interfering RNA had significantly increased (2.5-fold) CCL5/RANTES production compared with control HCECs, demonstrating a negative regulatory role for MyD88 in TLR3/TRIF responses in these cells. Finally, knockdown of MyD88 in HCECs resulted in increased phosphorylation of c-Jun N-terminal kinase (JNK), but not p38, IRF-3, or NF-B. Consistent with this finding, the JNK inhibitor SP600125, but not p38 inhibitor SB203580, ablated this response. Taken together, these findings demonstrate a novel JNK-dependent inhibitory role for MyD88 in the TLR3/TRIF activation pathway.

Received for publication, August 29, 2007 , and in revised form, November 28, 2007.

^* This work was supported in part by National Institutes of Health Grants RO1EY14362 (to E. P.), P30EY11373 (to E. P.), and RO1GM060020 (to X. L.), by the Research to Prevent Blindness Foundation, and by the Ohio Lions Eye Research Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Ophthalmology and Visual Sciences, Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH 44106-7286. Tel.: 216-368-1856; Fax: 216-368-3171; E-mail: eric.pearlman{at}case.edu.

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