Toll-like receptor-4 knockout mice are more resistant to optic nerve crush damage than wild-type mice

Dana Morzaev, James D. Nicholson, Tomm Caspi, Shirel Weiss, Edith Hochhauser, Nitza Goldenberg-Cohen

Research output: Contribution to journalArticlepeer-review

Abstract

Background: This study aims to investigate the role of the inflammatory response following optic nerve crush (ONC) in knockout mice for the toll-like receptor-4 gene (TLR4-/-) compared to wild-type (WT) mice. Methods: ONC was induced in TLR4-/- and C57BL6 WT mice. Histological sections of the retina and optic nerve were analysed on days 1, 3 or 21 after injury. Molecular analysis with real-time quantitative polymerase chain reaction was used to study the expression of CD45, tumour necrosis-alpha (TNF-α) and glial fibrillary acidic protein, as well as retinal ganglion cell (RGC) markers THY-1 and Brn3b. Results: There was a 25.5% and 38% loss in the RGC layer of the ONC-injured eyes of the TLR4-/- and the WT mice, respectively (with 27% and 9% of the remaining cells positive for Brn3a, respectively). Mean levels of Thy-1 and Brn3b were higher in the TLR4-/- mice. CD45 and Iba1 staining revealed infiltration of inflammatory cells into the injured nerve and retina in both groups. Molecular analysis of the optic nerve on day 1 showed increased TNF-α expression and reduced CD45 and GFAP expression; on day 3, CD45 reverted to baseline but GFAP remained low; on day 21, all 3 markers were at baseline in the TLR4-/- group and decreased in the WT group. Conclusion: Inflammation plays a major role in the response to ONC injury. Reduced levels of inflammation are associated with improved RGC preservation. The increase in TNF-α and reduction in CD45 in both TLR4-/- and WT mice may indicate the presence of an alternative pathway for induction of RGC death.

Original languageEnglish
Pages (from-to)655-665
Number of pages11
JournalClinical and Experimental Ophthalmology
Volume43
Issue number7
DOIs
StatePublished - 1 Sep 2015

Keywords

  • Ischemic retina
  • Neuroprotection
  • Optic nerve crush model
  • TLR-4 knockout mouse

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