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Damage-associated molecular pattern recognition is required for induction of retinal neuroprotective pathways in a sex-dependent manner.

ABSTRACT: Retinal degeneration is a common cause of irreversible blindness and is caused by the death of retinal light-sensitive neurons called photoreceptors. At the onset of degeneration, stressed photoreceptors cause retinal glial cells to secrete neuroprotective factors that slow the pace of degeneration. Leukemia inhibitory factor (LIF) is one such factor that is required for endogenous neuroprotection. Photoreceptors are known to release signals of cellular stress, called damage-associated molecular patterns (DAMPs) early in degeneration, and we hypothesized that receptors for DAMPs or pattern recognition receptors (PRRs) play a key role in the induction of LIF and neuroprotective stress responses in retinal glial cells. Toll-like receptor 2 (TLR2) is a well-established DAMP receptor. In our experiments, activation of TLR2 protected both male and female mice from light damage, while the loss of TLR2 in female mice did not impact photoreceptor survival. In contrast, induction of protective stress responses, microglial phenotype and photoreceptor survival were strongly impacted in male TLR2-/- mice. Lastly, using publicly available gene expression data, we show that TLR2 is expressed highly in resting microglia prior to injury, but is also induced in Müller cells in inherited retinal degeneration.

SUBMITTER: Hooper MJ

PROVIDER: S-EPMC6002365 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Damage-associated molecular pattern recognition is required for induction of retinal neuroprotective pathways in a sex-dependent manner.

Hooper Marcus J MJ Wang Jiangang J Browning Robert R Ash John D JD

Scientific reports 20180614 1

Retinal degeneration is a common cause of irreversible blindness and is caused by the death of retinal light-sensitive neurons called photoreceptors. At the onset of degeneration, stressed photoreceptors cause retinal glial cells to secrete neuroprotective factors that slow the pace of degeneration. Leukemia inhibitory factor (LIF) is one such factor that is required for endogenous neuroprotection. Photoreceptors are known to release signals of cellular stress, called damage-associated molecular ...[more]

PMID: 29904087

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Project description:Several studies have consistently reported a detrimental effect of chronic stress on recognition memory. However, the effects of acute stress on this cognitive ability have been poorly investigated. Moreover, despite well-documented sex differences in recognition memory observed in clinical studies, most of the preclinical studies in this field of research have been carried out by using solely male rodents. Here we tested the hypothesis that acute stress could affect the consolidation of different types of recognition memory in a sex-dependent manner. For this purpose, male and female C57BL6/J mice were exposed to 2-h of restrain stress immediately after the training session of both the novel object recognition (NOR) test and novel object location (NOL) tasks. Acute restraint stress did not affect memory performance of male and female mice, after a 4-h delay between the training session and the test phase of both tasks. By contrast, acute restraint stress altered memory performance in a sex-dependent manner, after a 24-h delay. While stressed mice of both sexes were impaired in the NOL test, only male stressed mice were impaired in the NOR test. Because ionotropic glutamate receptors-mediated neurotransmission is essential for shaping recognition memory, we further tested the hypothesis that post training acute stress could induce sex-dependent transcriptional changes of ionotropic glutamate receptor subunits in the dorsal hippocampus. We uncovered that acute stress induced sex-, time- and type of memory-dependent transcriptional changes of N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits. These findings suggest that the effect of acute stress on recognition memory can be strongly biased by multiple factors including sex. These findings also indicate that the same stress-induced memory impairment observed in both sexes can be triggered by different sex-dependent molecular mechanisms. At the therapeutic level, this should not be overlooked in the context of personalized and targeted treatments.

Dataset Information

Damage-associated molecular pattern recognition is required for induction of retinal neuroprotective pathways in a sex-dependent manner.

Publications

Damage-associated molecular pattern recognition is required for induction of retinal neuroprotective pathways in a sex-dependent manner.

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