Highlights d A cell-type-specific transcriptomic map of the cochlear response to noise d Noise-resilient type 1A auditory neurons upregulate the ATF3/4 pathway d Monocytes significantly alter their gene expression in response to noise exposure d STAT3/IRF7 are probable regulators of a general cochlear transcriptomic response to noise
Chronic neuroinflammation is a pathogenic component of Alzheimer's disease (AD) that may limit the ability of the brain to clear amyloid deposits and cellular debris. Tight control of the immune system is therefore key to sustain the ability of the brain to repair itself during homeostasis and disease. The immune-cell checkpoint receptor/ligand pair PD-1/PD-L1, known for their inhibitory immune function, is expressed also in the brain. Here, we report upregulated expression of PD-L1 and PD-1 in astrocytes and microglia, respectively, surrounding amyloid plaques in AD patients and in the APP/PS1 AD mouse model. We observed juxtamembrane shedding of PD-L1 from astrocytes, which may mediate ectodomain signaling to PD-1-expressing microglia. Deletion of microglial PD-1 evoked an inflammatory response and compromised amyloidb peptide (Ab) uptake. APP/PS1 mice deficient for PD-1 exhibited increased deposition of Ab, reduced microglial Ab uptake, and decreased expression of the Ab receptor CD36 on microglia. Therefore, ineffective immune regulation by the PD-1/PD-L1 axis contributes to Ab plaque deposition during chronic neuroinflammation in AD.
SUMMARY
The cochlea possesses a robust circadian clock machinery that regulates
auditory function. How the cochlear clock is influenced by the circadian system
remains unknown. Here we show that cochlear rhythms are system-driven and
require local Bmal1 as well as central input from the
suprachiasmatic nuclei (SCN). SCN ablations disrupted the circadian expression
of the core clock genes in the cochlea. Since the circadian secretion of
glucocorticoids (GCs) is controlled by the SCN and that GCs are known to
modulate auditory function, we assessed their influence on circadian gene
expression. Removal of circulating GCs by adrenalectomy (ADX) did not have a
major impact on core clock gene expression in the cochlea. Rather it abolished
the transcription of clock-controlled genes involved in inflammation. ADX
abolished the known differential auditory sensitivity to day and night noise
trauma and prevented the induction of GABA-ergic and glutamate receptors mRNA
transcripts. However, these improvements were unrelated to changes at the
synaptic level suggesting other cochlear functions may be involved. Due to this
circadian regulation of noise sensitivity by GCs, we evaluated the actions of
the synthetic glucocorticoid dexamethasone (DEX) at different times of the day.
DEX was effective in protecting from acute noise trauma only when administered
during daytime, when circulating glucocorticoids are low, indicating that
chronopharmacological approaches are important for obtaining optimal treatment
strategies for hearing loss. GCs appear as a major regulator of the differential
sensitivity to day or night noise trauma, a mechanism likely involving the
circadian control of inflammatory responses.
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