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James T. Rosenbaum, Jelena Kezic, Stanford Taylor, Seema Gupta, Stephen R. Planck, Holly Rosenzweig; Endotoxin-induced Uveitis Is Primarily Independent Of Bone-marrow-derived Cells And Dependent On Myd88 But Not Trif. Invest. Ophthalmol. Vis. Sci. 2011;52(14):4766.
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TLR4 activation by lipopolysaccharide (LPS, endotoxin) is mediated by both the MyD88 and TRIF intracellular signaling pathways. We determined if there is a difference in the relative activation of the two TLR4 pathways in murine ocular tissue after systemic or local LPS treatment. Additionally, we explored whether bone marrow-derived ocular cells (e.g., macrophages and dendritic cells) or non-bone marrow-derived ocular cells, (e.g., iris epithelial and endothelial cells) were major contributors to endotoxin-induced uveitis (EIU).
Mice deficient in TIR-domain-containing adapter-inducing interferon-β (TRIF) or myeloid differentiation factor 88 (MyD88) and their wild-type (WT) controls were administered 250 ng of ultrapure LPS intravitreally (local) or 100 µg intraperitoneally (systemically) at 0 h. Ocular inflammation was assessed by histological analysis at 4 h, 6 h 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 at 4 h. Bone marrow chimeric mice (WT→WT, TLR4-/-→WT, WT→TLR4-/-) were administered 250 ng of LPS by local injection and ocular tissues were examined by histology at 6 h.
Intravital microscopic examination and histological analysis revealed a markedly diminished inflammatory response in the absence of MyD88. This was accompanied by reduced production of MyD88-related cytokines 4 h post-LPS treatment. In contrast, the absence of TRIF led to reduced production of TRIF-related cytokines but no reduction in the cellular response to LPS. Bone marrow chimeric studies revealed abolishment of LPS-induced inflammation only in WT→TLR4-/- chimeric mice suggesting that non-bone marrow-derived cells within the eye are the essential mediators of EIU.
Despite both MyD88 and TRIF related cytokines being produced in the eye in response to locally and systemically administered LPS, the MyD88 pathway appears to be the dominant TLR4 signaling pathway during EIU. Surprisingly, non-bone marrow-derived cells in the eye play a greater role than bone marrow-derived cells in the development of EIU. Further clarification of regulatory mechanisms controlling the ocular response to LPS exposure is fundamental to our understanding of immune responses in the eye.
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