Toll-like receptor-9 (TLR-9) deficiency alleviates optic nerve injury (ONI) by inhibiting inflammatory response in vivo and in vitro.

Publisher: Academic Press Country of Publication: United States NLM ID: 0373226 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1090-2422 (Electronic) Linking ISSN: 00144827 NLM ISO Abbreviation: Exp Cell Res Subsets: MEDLINE

Publication: Orlando Fl : Academic Press
Original Publication: New York, Academic Press.

Microglia/*metabolism ; Myeloid Differentiation Factor 88/*genetics ; Optic Nerve/*metabolism ; Optic Nerve Injuries/*genetics ; Retinal Ganglion Cells/*metabolism ; Toll-Like Receptor 9/*genetics; Animals ; Calcium-Binding Proteins/genetics ; Calcium-Binding Proteins/metabolism ; Cell Count ; Chemokine CCL2/genetics ; Chemokine CCL2/metabolism ; Cyclooxygenase 2/genetics ; Cyclooxygenase 2/metabolism ; Gene Expression Regulation ; I-kappa B Kinase/genetics ; I-kappa B Kinase/metabolism ; Inflammation ; Interleukin-1 Receptor-Associated Kinases/genetics ; Interleukin-1 Receptor-Associated Kinases/metabolism ; Interleukin-18/genetics ; Interleukin-18/metabolism ; Interleukin-1beta/genetics ; Interleukin-1beta/metabolism ; Male ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Microfilament Proteins/genetics ; Microfilament Proteins/metabolism ; Microglia/pathology ; Myeloid Differentiation Factor 88/metabolism ; Nitric Oxide Synthase Type II/genetics ; Nitric Oxide Synthase Type II/metabolism ; Optic Nerve/pathology ; Optic Nerve Injuries/metabolism ; Optic Nerve Injuries/pathology ; Retinal Ganglion Cells/pathology ; Signal Transduction ; Toll-Like Receptor 9/deficiency ; Transcription Factor Brn-3A/genetics ; Transcription Factor Brn-3A/metabolism ; Tumor Necrosis Factor-alpha/genetics ; Tumor Necrosis Factor-alpha/metabolism

Traumatic optic neuropathy is a common clinical problem. Damage to the optic nerve leads to shear stress and triggers secondary swelling within the optic canal. The study aims to explore the role of the inflammatory response following optic nerve injury (ONI) in toll-like receptor-9 knockout mice (TLR-9 ^-/- ) compared to wild-type mice (WT). At first, TLR-9 ^-/- and WT mice were subjected to ONI. We then found that ONI significantly up-regulated TLR-9 expression levels in retinal tissues of WT mice. The retinal degeneration after ONI was alleviated in TLR-9 ^-/- mice, as evidenced by the increased number of retinal ganglion cells (RGCs) and thickness of inner retinal layer (IRL). TUNEL staining and immunofluorescence staining of BRN3A indicated that TLR-9 knockout effectively improved the survival of RGCs. ONI-enhanced expression of Iba-1 and TMEM119 was markedly reduced in TLR-9 ^-/- mice, indicating the suppression of microglial activation. Moreover, production of pro-inflammatory regulators, including inducible nitric oxide synthase (iNOS), macrophage chemo-attractant protein (MCP)-1, cyclooxygenase-2 (COX-2), interleukin (IL)-1β, IL-18 and tumor necrosis factor-α (TNF-α), was significantly decreased in TLR-9 ^-/- mice following ONI. TLR-9 knockout-attenuated inflammation was mainly through repressing myeloid differentiation factor 88 (MyD88) and IL-1 receptor-associated kinase 4 (IRAK4). Furthermore, ONI greatly up-regulated the protein expression levels of phosphorylated (p)-IKKα, p-IκBα and p-nuclear factor (NF)-κB, whereas being repressed in TLR-9 ^-/- mice. The effects of TLR-9 on ONI were verified in lipopolysaccharide (LPS)-stimulated retinal microglial cells transfected with small interfering RNA TLR-9 (siTLR-9). As expected, promoting TLR-9 with its agonist markedly restored inflammation in TLR-9 knockdown cells stimulated by LPS. Therefore, all findings above suggested that suppressing TLR-9 showed neuroprotective effects against ONI through reducing inflammatory response, and TILR-9 might be a promising therapeutic target to develop effective strategies for the treatment of optic neuropathies.
(Copyright © 2020. Published by Elsevier Inc.)

Keywords: Inflammation; MyD88/IRAK4; NF-κB; Optic nerve injury; TLR-9

0 (Aif1 protein, mouse)
0 (Calcium-Binding Proteins)
0 (Ccl2 protein, mouse)
0 (Chemokine CCL2)
0 (IL1B protein, mouse)
0 (Interleukin-18)
0 (Interleukin-1beta)
0 (Membrane Proteins)
0 (Microfilament Proteins)
0 (Myd88 protein, mouse)
0 (Myeloid Differentiation Factor 88)
0 (Obif protein, mouse)
0 (Pou4f1 protein, mouse)
0 (Tlr9 protein, mouse)
0 (Toll-Like Receptor 9)
0 (Transcription Factor Brn-3A)
0 (Tumor Necrosis Factor-alpha)
EC 1.14.13.39 (Nitric Oxide Synthase Type II)
EC 1.14.13.39 (Nos2 protein, mouse)
EC 1.14.99.- (Ptgs2 protein, mouse)
EC 1.14.99.1 (Cyclooxygenase 2)
EC 2.7.11.1 (Interleukin-1 Receptor-Associated Kinases)
EC 2.7.11.1 (Irak4 protein, mouse)
EC 2.7.11.10 (I-kappa B Kinase)

Date Created: 20200712 Date Completed: 20210311 Latest Revision: 20210311

20240829

10.1016/j.yexcr.2020.112159

32652081