Myd88 Deficiency Accelerates Retinal Degeneration and Alters Microglial Dynamics in a Mouse Model of Retinitis Pigmentosa

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.