Abstract
Prion diseases are caused by the misfolding of a normal host protein that leads to gliosis, neuroinflammation, neurodegeneration, and death. Microglia have been shown to be critical for neuroprotection during prion infection of the central nervous system (CNS), and their presence extends survival in mice. How microglia impart these benefits to the infected host are unknown. Previous transcriptomics and bioinformatics studies suggested that signaling through the heterodimeric integrin receptor CD11c/CD18, expressed by microglia in the brain, might be important to microglial function during prion disease. Herein, we intracerebrally challenged CD11c-/- mice with prion strain RML and compared them to similarly infected C57BL/6 mice as controls. We initially assessed changes in the brain that are associated with disease such as astrogliosis, microgliosis, prion accumulation, and survival. Targeted qRT-PCR arrays were used to determine alterations in transcription in mice in response to prion infection. We demonstrate that expression of Itgax (CD11c) and Itgb2 (CD18) increases in the CNS in correlation with advancing prion infection. Gliosis, neuropathology, prion deposition, and disease progression in prion infected CD11c deficient mice were comparable to infected C57BL/6 mice. Additionally, both CD11c deficient and C57BL/6 prion-infected mouse cohorts had a similar consortium of inflammatory- and phagocytosis-associated genes that increased as disease progressed to clinical stages. Ingenuity Pathway Analysis of upregulated genes in infected C57BL/6 mice suggested numerous cell-surface transmembrane receptors signal through Spleen Tyrosine Kinase, a potential key regulator of phagocytosis and innate immune activation in the prion infected brain. Ultimately, the deletion of CD11c did not influence prion pathogenesis in mice and CD11c signaling is not involved in the neuroprotection provided by microglia, but our analysis identified a conspicuous phagocytosis pathway in the CNS of infected mice that appeared to be activated during prion pathogenesis.