Abstract Title

Crosstalk Between TGFβ2 and TLR4 in the Trabecular Meshwork

Presenter Name

Amanda L. Roberts

RAD Assignment Number

908

Abstract

Purpose: The trabecular meshwork (TM) regulates aqueous humor outflow and intraocular pressure (IOP). The effects of TGFβ signaling pathways on the TM extracellular matrix (EÇM) have been extensively studied. Recently, we identified TGFβ2 and toll-like receptor 4 (TLR4) signaling crosstalk regulates changes in the TM ECM and mutation in Tlr4 rescues TGFβ2 -induced ocular hypertension in mice. Here, we investigated the role of an endogenous TLR4 ligand, FN-EDA, and a downstream signaling molecule of TLR4, NFκB, in TGFβ2 -induced ocular hypertension in mice.

Methods: B6.FN-EDA-/- (n=18), B6.FN-EDA+/+/TLR4-/- (n=7), B6.FN-EDA-/-/ TLR4-/- (n=15), and C57BL/6J (n=11) mice were intravitreally injected with 2.0 μL Ad5.TGFβ2 (2.5x107 pfu) in one eye and the contralateral uninjected eye was used as a negative control. Likewise, we tested mice lacking the p50 subunit of NFκB (B6.Cg-NFκB1tm1Bal/J) (n=7) and C57BL/6J (n=10) mice. IOP was measured using a TonoLab rebound tonometer on isoflurane-anesthetized mice for 42 days post-injection. Significance determined by one-way ANOVA at each time point.

Results: Ad5.TGFβ2 significantly induced ocular hypertension in C57BL/6J mice in both experiments. In the first experimental cohort, Ad5.TGFβ2 significantly induced ocular hypertension in C57BL/6J mice starting at 7-days post injection and remained significant until 42 days post-injection (p

Conclusions: These findings demonstrate that TLR4, the endogenous TLR4 ligand FN-EDA, and NFκB are necessary for TGFβ2 induced ocular hypertension in mice. These data provide potential new targets to lower IOP and to further explore the molecular mechanisms involved in the development of glaucomatous TM damage.

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Research Area

Eye/Vision

Presentation Type

Poster

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Crosstalk Between TGFβ2 and TLR4 in the Trabecular Meshwork

Purpose: The trabecular meshwork (TM) regulates aqueous humor outflow and intraocular pressure (IOP). The effects of TGFβ signaling pathways on the TM extracellular matrix (EÇM) have been extensively studied. Recently, we identified TGFβ2 and toll-like receptor 4 (TLR4) signaling crosstalk regulates changes in the TM ECM and mutation in Tlr4 rescues TGFβ2 -induced ocular hypertension in mice. Here, we investigated the role of an endogenous TLR4 ligand, FN-EDA, and a downstream signaling molecule of TLR4, NFκB, in TGFβ2 -induced ocular hypertension in mice.

Methods: B6.FN-EDA-/- (n=18), B6.FN-EDA+/+/TLR4-/- (n=7), B6.FN-EDA-/-/ TLR4-/- (n=15), and C57BL/6J (n=11) mice were intravitreally injected with 2.0 μL Ad5.TGFβ2 (2.5x107 pfu) in one eye and the contralateral uninjected eye was used as a negative control. Likewise, we tested mice lacking the p50 subunit of NFκB (B6.Cg-NFκB1tm1Bal/J) (n=7) and C57BL/6J (n=10) mice. IOP was measured using a TonoLab rebound tonometer on isoflurane-anesthetized mice for 42 days post-injection. Significance determined by one-way ANOVA at each time point.

Results: Ad5.TGFβ2 significantly induced ocular hypertension in C57BL/6J mice in both experiments. In the first experimental cohort, Ad5.TGFβ2 significantly induced ocular hypertension in C57BL/6J mice starting at 7-days post injection and remained significant until 42 days post-injection (p

Conclusions: These findings demonstrate that TLR4, the endogenous TLR4 ligand FN-EDA, and NFκB are necessary for TGFβ2 induced ocular hypertension in mice. These data provide potential new targets to lower IOP and to further explore the molecular mechanisms involved in the development of glaucomatous TM damage.