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Sarah Syeda, Amit K Patel, Abigail S Hackam; Deleting the TLR/MYD88 Branch of Innate Immunity Preserves Retinal Function in the rd1 and rd10 mouse. Invest. Ophthalmol. Vis. Sci. 2014;55(13):4375.
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© ARVO (1962-2015); The Authors (2016-present)
Toll-Like Receptors (TLRs) form a key branch of innate immunity, the dysregulation of which has been implicated in the pathogenesis of retinal degeneration. Most TLRs operate through the adaptor protein Myeloid differentiation primary response gene 88 (MYD88) whose downstream mediators induce pro and anti-inflammatory genes. The purpose of this study is to examine the role of MYD88 signaling in the retinal degeneration 1 (rd1) and rd10 mouse models. We hypothesize that knockout of this TLR/MYD88 innate immunity pathway will protect retinal function.
We bred rd1 and rd10 mice with MYD88-/- mice to produce mice homozygous for the rd1 or rd10 mutation, and MYD88+/+, MYD88+/-, and MYD88-/- genotypes. Electroretinograms (ERG) were performed at different time points to investigate retinal function. Retinas were then taken for protein analysis by Western blot, and for chemokine mRNA analysis by qRT-PCR. Fellow eyes were sectioned for microglia staining with IBA-1.
ERGs show preservation of photopic function at postnatal day (P) 13/14 in rd1 rd1/MYD88-/- mice (n=14) compared with rd1/MYD88+/+ (n=11, p<0.05) and also in rd10/MYD88-/- mice (n=3) compared with rd10/MYD88+/+ (n=7, p=0.022) at P19-30. Cone transducin (Gαt2) protein levels in rd1/MYD88-/- mice (P13, P14 n=3) were 2-fold higher compared with rd1/MYD88+/+ (P13, n=3; P14, n=4), and also in rd10/MYD88-/- mice (n=2) compared with rd10/MYD88+/+ (n=4) indicating rescued cone photoreceptors. Chemokine analysis showed a 2 to 5-fold reduction in CCL4, CCL5, CCL7, CxCL10 and TNFα mRNA levels at P12 in rd1/MYD88-/- mice (n=3) compared with rd1/MYD88+/+ (n=3, p<0.05). There was no difference in the number of activated microglia in outer retinal layers of rd1/MYD88-/- mice (n=3) compared with rd1/MYD88+/+ (n=4) at P14, as indicated by IBA-1 staining, suggesting that the protective effect of blocking TLR/MYD88 signaling is independent of microglia-induced exacerbation of photoreceptor death in the rd1 mouse.
This study shows that knocking out the TLR innate immunity pathway via MYD88 protects retinal function in the rd1 and rd10 mouse by diminishing the destructive effect of MYD88-dependent chemokines. In conclusion, we introduce the TLR/MYD88 signaling pathway as a potential target for future therapeutic strategies for retinal degenerative conditions.
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