Endotoxin-induced uveitis is primarily dependent on radiation-resistant cells and on MyD88 but not TRIF
Open Access
- 24 May 2011
- journal article
- research article
- Published by Oxford University Press (OUP) in Journal of Leukocyte Biology
- Vol. 90 (2), 305-311
- https://doi.org/10.1189/jlb.0111036
Abstract
TLR4 activation by LPS (endotoxin) is mediated by the MyD88 and TRIF intracellular signaling pathways. We determined the relative activation of these pathways in murine ocular tissue after LPS exposure. Additionally, we explored whether BM‐derived or non‐BM‐derived cells were the major contributors to EIU. Mice deficient in TRIF or MyD88 and their congenic (WT) controls received 250 ng ultrapure LPS ivt at 0 h. Ocular inflammation was assessed by histological analysis at 4, 6, and 24 h, and additionally, in MyD88−/− mice, intravital microscopy was performed at 4 h and 6 h to assess adherent, rolling, and infiltrating cells in the iris vasculature and tissue. Cytokines associated with the MyD88 and TRIF intracellular signaling pathways were analyzed in ocular tissue at 4 h. BM chimeric mice (WT→WT, TLR4−/−→WT, WT→TLR4−/−) received 250 ng LPS by ivt injection, and ocular tissues were examined by histology at 6 h. Lack of MyD88 resulted in a markedly diminished cellular response and reduced production of MyD88‐related cytokines 4 h post‐LPS treatment. In contrast, lack of TRIF led to reduced production of TRIF‐related cytokines and no change in the cellular response to LPS. Therefore, the MyD88 pathway appears to be the dominant TLR4 pathway in EIU. Only WT → TLR4−/− chimeric mice were resistant to EIU, and this suggests, surprisingly, that non‐BM‐derived (radiation‐resistant) cells in the eye play a greater role than BM‐derived cells.Keywords
Funding Information
- NIH (EY019604, EY010572)
- Oregon Clinical and Translational Research Institute (TL1 RR024159)
- National Center for Research Resources
- NIH
- NIH Roadmap for Medical Research
- Research to Prevent Blindness
- William C. Kuzell Foundation
- William and Mary Bauman Foundation
- Stan and Madelle Rosenfeld Family Trust
- American College of Rheumatology and Research to Prevent Blindness
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