Interferon regulator factor (IRF) 8 regulates the microglial response to neuronal injury — ASN Events
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  3. Interferon regulator factor (IRF) 8 regulates the microglial response to neuronal injury

Interferon regulator factor (IRF) 8 regulates the microglial response to neuronal injury (#202)

Rui Dan Xie 1 , Nàdia Villacampa 2 , Beatriz Almolda 2 , Berta González 2 , Bernardo Castellano 2 , Iain L. Campbell
  1. School of Molecular Bioscience, University of Sydney, Camperdown, NSW, Australia
  2. Medical Histology, Institut de Neurociències, Universitat Autònoma de Barcelona, Barcelona, Spain

The transcription factor interferon regulatory factor (IRF) 8 has a key role in the cellular response to IFN-γ and is involved in myeloid cell differentiation. We have previously identified IRF8 to be a constitutive and IFN-γ-stimulated nuclear factor that regulates the homeostatic properties of microglia. Our study aimed to determine the role of IRF8 in the microglial response to sterile neuronal injury.

Facial nerve axotomy (FNA) was performed in wildtype (WT) and IRF8-/- (KO) mice and the brains removed at different times post-lesion. A subset of mice was injected with bromodeoxyuridine (BrdU) prior to retrieval of the brain. Changes in the facial nucleus (FN) were examined by immunohistochemistry and histochemistry.

In brains from IRF8KO mice, nucleoside diphosphatase (NDPase) hisotchemistry revealed gross alterations in the morphology of microglia, which were stunted and hypertrophied. After FNA in WT mice, a progressive increase in microglial activation was observed in the lesioned FN peaking at day 7 and was accompanied by dense staining for Iba1, lectin, NDPase and CD11b. By contrast, in IRF8KO mice, the microglial response was markedly attenuated with little staining for Iba1, while the density of staining for lectin and NDPase was reduced significantly. The attenuated microglial response in IRF8KO mice was paralleled by a significant decrease at day 3 post-lesion in proliferation as monitored by BrdU, phosphohistone 3 and Ki67-positive cells. Furthermore, a decrease in PU.1-positive cells was observed in the FN of IRF8KO mice compared with WT. The wrapping of individual motor neuron cell bodies by microglia involved in synaptic stripping and phagocytosis was incomplete in the absences of IRF8 in the axotomised FN. Quantitative analysis showed that in IRF8KO mice, the degeneration of axotomised motor neurons was significantly increased.

These studies extend on our previous finding that IRF8 is a key homeostatic transcription regulator of microglial cell function in the healthy brain, and moreover, has a crucial role in the regulating the response to microglia to neuronal injury.