Glial immune signaling in radiation-induced brain injury

ABSTRACT: Glial immune signaling in radiation-induced brain injury.
Cranial radiation therapy (CRT) for the treatment of CNS cancers often leads to unintended and
debilitating cognitive impairments. CRT also remains the standard of care to counter brain
metastases for other invasive cancers. However, the molecular and cellular mechanisms
underlying CRT-induced cognitive decline are multifaceted and have not been completely
resolved. Our past findings show that whole-brain, acute CRT induces progressive
neurodegenerative changes, including oxidative stress, reduced neurogenesis, and increased
neuroinflammation. Microglia and astrocytes form complex glial networks in the CNS by pruning
and maintaining thousands of synapses that are actively involved in cognition. Yet, we have
shown that CRT-induced cognitive disruption coincides with astrocytic hypertrophy, elevated
expression of astrogliosis genes, and persistent microglial activation in rodent models. Therefore,
we hypothesize that detrimental glial signaling significantly contributes to cognitive deficits. The
complement system is a potent mediator of the glial activation, but it also has a range of non-
immune functions in the CNS, including synaptic pruning and clearance of apoptotic cells and
cellular debris which is detrimental if dysregulated. Particularly, global elevation in the expression
of complement C1q and C3 in the CNS has been reported in neurodegenerative conditions. Our
findings indicate that acute, whole-brain CRT-mediated chronic microglial activation and reactive
astrocytes, elevated co-expression of complement proteins (C1q, C3) and specific receptors
(C5aR1, TLR4) coincided with cognitive impairments. Reactive gliosis has been shown to
upregulate complement cascade proteins that are destructive to synapses and associated with
neurodegeneration. We hypothesize that brain cancer therapy-induced aberrant activation in the
glial complement cascade leads to cognitive deficits. Our hypothesis is supported by two key
preliminary data sets targeting complement signaling at the upstream (C1q) and the downstream
(C5a) activation branch points. First, exposure of conditional microglia-selective C1q (knockdown)
mice to CRT did not exhibit impaired cognition and showed a lack of neuroinflammation as
compared to irradiated WT mice. Second, treatment with an orally active, BBB permeable, C5a
receptor (C5aR1) antagonist ameliorated acute CRT-induced cognitive deficits and alleviated
microglial activation in the irradiated brain. Our hypothesis will be addressed using a clinically
relevant, fractionated, focal cranial irradiation paradigm ± temozolomide, transgenic and glioma-
bearing syngeneic mouse models, and pharmacologic approaches designed to test mechanisms
and therapeutic interventions to restore cognitive function in the impaired animals.

Grant Number: 5R01CA251110-05
NIH Institute/Center: NIH
Principal Investigator: Munjal Acharya