Abstract
Purpose :
Neuroinflammation is triggered by the recognition of damage-associated molecular patterns (DAMPs) by the pattern recognition receptors (PRRs). Toll-like receptors (TLRs)/MyD88 and C-type lectin receptors (CLRs)/Card9 are two major PRR pathways that mediate inflammatory signaling in tissue injury and repair. In the present study, we investigated the respective functions of MyD88 and Card9 in retinal degeneration and neuroinflammation in a mouse model of retinitis pigmentosa (RP).
Methods :
Rd10 mice, a RP model harboring Pde6b mutation, were crossed with Myd88-/- or Card9-/- mice to produce rd10; Myd88-/- or rd10; Card9-/- mice. The retinal phenotype was assessed by TUNEL, HE staining and electroretinogram (ERG). Retinal microglia were immunostained with Iba-1. Retinal mRNA profiles associated with neuroinflammation were analyzed by using nCounter Nano String Neuroinflammation panels. Immunostaining for the differential expressed genes was performed on retinal sections.
Results :
Mdy88 deficiency in rd10 mice increased the number of TUNEL-positive cells in the outer nuclear layer (ONL) and exacerbated ONL thinning at P21 (P < 0.01, each); whereas Card9 deficiency did not influence the retinal phenotype. Consistently, scotopic ERG showed that b-wave amplitudes were decreased in rd10; Myd88-/- mice compared to rd10 mice (P=0.002), while there was no difference between rd10; Card9-/- and rd10 mice. Microglial translocation to the outer retina was significantly decreased in rd10; Myd88-/- compared to rd10 mice(P < 0.01). Retinal mRNA profiling identified increased expression of Ifitm3 and Serpina3n, activation 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 :
TLRs/MyD88 pathway, but not CLRs/Card9 pathway, is a key mediator of neuroinflammation in rd10 mice, and may provide neuroprotection via promoting microglial translocation and regulating astrocyte/müller cell activation in RP.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.