Myd88 Deficiency Accelerates Retinal Degeneration and Alters Microglial Dynamics in a Mouse Model of Retinitis
Shotaro Shimokawa1, Sakurako Shimokawa1, Huanyu Zhao1
1Department of Ophthalmology, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan.
Purpose:
Neuroinflammation is triggered by the recognition of damage-associated molecular patterns (DAMPs) by pattern recognition receptors (PRRs). Toll-like receptors (TLRs)/MyD88 is the PRR pathway that mediates inflammatory signaling. We investigated the functions of Myd88 in retinal degeneration and neuroinflammation in a mouse model of retinitis pigmentosa (RP).
Methods:
Rd10 mice were crossed with Myd88-/- mice to produce rd10; Myd88-/- mice. The retinal phenotype was assessed by TUNEL, hematoxylin and eosin (H&E) staining, and electroretinography. Retinal microglia were immunostained with Iba-1. Retinal mRNA profiles associated with neuroinflammation were analyzed using a NanoString Neuroinflammation panel.
Results:
Myd88 deficiency increased the number of TUNEL-positive cells in the outer nuclear layer (ONL) and exacerbated ONL thinning at postnatal day 18 and 21 (P < 0.01, each). Consistent with these findings, the scotopic electroretinogram (ERG) showed lower b-wave amplitudes in rd10; Myd88-/- mice compared with rd10 mice (P < 0.01). Microglial infiltration into the outer retina showed an early but transient increase at P18, followed by a reduction at P21 in rd10; Myd88-/- mice. Retinal mRNA profiling revealed increased expression of Ifitm3 and Serpina3n, markers of astrocytic glia, in rd10; Myd88-/- mice. Immunostaining confirmed the upregulation of IFITM3 and SERPINA3N in astrocytes and Müller cells in rd10; Myd88-/- mice.
Conclusions:
Myd88 deficiency accelerates retinal degeneration in rd10 mice, accompanied by an earlier onset of microglial infiltration and altered glia-related gene expression.
Insights
MyD88 deficiency accelerates retinal degeneration in a mouse model of retinitis pigmentosa. This involves earlier microglial infiltration and changes in glia gene expression, worsening the condition.
Area of Science:
- Ophthalmology
- Neuroscience
- Immunology
Background:
- Neuroinflammation, triggered by damage-associated molecular patterns (DAMPs) binding to pattern recognition receptors (PRRs), plays a role in retinal degeneration.
- The Toll-like receptor (TLR)/MyD88 pathway is a key mediator of inflammatory signaling in neuroinflammation.
Purpose of the Study:
- To investigate the role of MyD88 in retinal degeneration and associated neuroinflammation.
- To analyze the impact of MyD88 deficiency on the rd10 mouse model of retinitis pigmentosa (RP).
Main Methods:
- Rd10 mice were crossed with MyD88 knockout mice (Myd88-/-) to create rd10; Myd88-/- mice.
- Retinal phenotype was assessed using TUNEL assay, H&E staining, and electroretinography (ERG).
- Microglia and glial markers were analyzed via immunostaining and NanoString Neuroinflammation panel for gene expression profiling.
Main Results:
- MyD88 deficiency significantly increased cell death (TUNEL-positive cells) and thinning of the outer nuclear layer (ONL) in rd10 mice.
- Scotopic ERG showed reduced b-wave amplitudes in rd10; Myd88-/- mice, indicating worsened visual function.
- An early but transient increase in microglial infiltration was observed, along with upregulation of astrocytic glia markers (Ifitm3, Serpina3n) in the retinas of rd10; Myd88-/- mice.
Conclusions:
- MyD88 deficiency accelerates retinal degeneration in the rd10 mouse model of RP.
- The absence of MyD88 leads to an earlier onset of microglial infiltration and altered glial gene expression, contributing to disease progression.