Neuroprotective roles of fractalkine in multiple sclerosis: Characterization of novel humanized animal model

Autor: Sandra M. Cardona, Sangwon V. Kim, Vanessa Torres, Chiung-Yu Hung, Kaira Church, Ian Cleary, Andrew S. Mendiola, Stephen Saville, Stephanie S. Watowich, Jan Parker-Thornburg, Dan R. Littman, Richard M. Ransohoff, Astrid E. Cardona
Rok vydání: 2018
Předmět:
Zdroj: The Journal of Immunology. 200:108.22-108.22
ISSN: 1550-6606
0022-1767
DOI: 10.4049/jimmunol.200.supp.108.22
Popis: Multiple sclerosis (MS), an inflammatory demyelinating disease of the CNS is the leading cause of nontraumatic neurological disability in young adults. Immune mediated destruction of the myelin and oligodendrocytes are considered its primary pathology, but progressive axonal loss is the major cause of neurological disability. In an effort to understand microglia function in CNS inflammation, our laboratory showed that Fractalkine/CX3CR1 signaling regulates microglia neurotoxicity during neurodegeneration. Fractalkine (FKN), a transmembrane chemokine expressed in the CNS by neurons signals through its unique receptor, CX3CR1 present in microglia. During EAE, CX3CR1 deficiency confers exacerbated disease, severe inflammation and neuronal loss. The CX3CR1 human polymorphism I249/M280 present in ~20% of the population exhibits reduced adhesion for FKN conferring defective signaling whose role in microglia function and effect on neurons during MS remains unsolved. The aim of this study is to assess the effect of weaker signaling through hCX3CR1I249/M280 during EAE. We hypothesize that dysregulated microglial responses in absence of CX3CR1 signaling enhance neuronal/axonal damage. We generated an animal model replacing the mouse CX3CR1 locus for the hCX3CR1I249/M280 variant. Upon EAE induction, these mice exhibit exacerbated EAE defined by severe inflammation and neuronal loss. We also observed that mice with aberrant CX3CR1 signaling are unable to produce FKN and CNTF during EAE as WT mice. Our results provide validation of defective function of the hCX3CR1I249/M280 variant and the foundation to broaden the understanding of microglia dysfunction during neuroinflammation.
Databáze: OpenAIRE
Externí odkaz: