AUTOPHAGY REGULATES MICROGLIAL PHAGOCYTOSIS OF APOPTOTIC CELLS IN PHYSIOLOGY AND ISCHEMIC STROKE PATHOLOGY

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Neuroimmune responses are critical for resilience against neurotropic infections.Conversely, dysregulated neuroimmune responses can promote vulnerability, inducing significant damage and even death.The neuroimmune mechanisms driving resilience and vulnerability to neurotropic infections are not well understood.We and others have shown that time of day of exposure to inflammatory stimuli or viruses impact immune responses and survival.Thus, time of day can be used to elucidate mechanisms of resilience and vulnerability to neurotropic viruses.Here, we investigate how time of day impacts neuroimmune responses of the olfactory bulb (OB), the site of neurotropic virus entry into the brain via the olfactory pathway.Our preliminary work demonstrated that 20% of the neuroinflammation-related transcriptional profile in the OB is rhythmically expressed, including transcripts enriched in interferon signaling and microglia function.Given these oscillations of neuroinflammation-related genes, we hypothesized that time of day would prime the OB to mount differential interferon and microglial responses to an acute intranasal poly(I:C) challenge.Using Nano-String technology, we determined time of day of intranasal poly(I:C) challenge alters the OB's neuroinflammation-related transcriptional response.Specifically, while some interferon-stimulated genes (Irf7, Ifitm3) were induced by intranasal poly(I:C) at the onset of the resting phase (ZT0) and the onset of the active phase (ZT12), others (Cxcl10, Ddx58, Oas1g, Rsad2, Ifih1) were induced only at ZT12.Given microglia sensome-related genes were rhythmically expressed in the OB, we hypothesized that OB microglia would respond differently to intranasal poly(I:C) depending on time of day.Using imaging flow cytometry, we observed a greater change in CD11b surface expression by OB microglia in response to intranasal poly(I: C) at ZT12 versus ZT0.We conclude time of day primes the OB to differentially mount neuroimmune responses to intranasal inflammatory stimuli.This priming may provide a gating mechanism underlying differential susceptibility to neurotropic virus exposure via the nasal route.

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