Role of the Fractalkine Receptor in CNS Autoimmune Inflammation: New Approach Utilizing a Mouse Model Expressing the Human CX3CR1^I249/M280 Variant

Authors

Sandra M. Cardona, University of Texas at San Antonio
Sangwon V. Kim, Thomas Jefferson University
Kaira A. Church, University of Texas at San Antonio
Vanessa O. Torres, University of Texas Southwestern Medical Center
Ian A. Cleary, Grand Valley State UniversityFollow
Andrew S. Mendiola, University of Texas at San Antonio
Stephen P. Saville, University of Texas at San Antonio
Stephanie S. Watowich, University of Texas MD Anderson Cancer Center
Jan Parker-Thornburg, University of Texas MD Anderson Cancer Center
Alejandro Soto-Ospina, University EIA
Richard M. Ransohoff, Third Rock Ventures
Astrid E. Cardona, University of Texas at San Antonio

Keywords

EAE (experimental autoimmune encephalitis), fractalkine receptor, microglia, multiple sclerosis and neuroimmunology, demyelination and neuronal damage

Disciplines

Molecular and Cellular Neuroscience

Abstract

Multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS) is the leading cause of non-traumatic neurological disability in young adults. Immune mediated destruction of myelin and oligodendrocytes is considered the primary pathology of MS, but progressive axonal loss is the major cause of neurological disability. In an effort to understand microglia function during CNS inflammation, our laboratory focuses on the fractalkine/CX3CR1 signaling as a regulator of microglia neurotoxicity in various models of neurodegeneration. Fractalkine (FKN) is a transmembrane chemokine expressed in the CNS by neurons and signals through its unique receptor CX3CR1 present in microglia. During experimental autoimmune encephalomyelitis (EAE), CX3CR1 deficiency confers exacerbated disease defined by 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 influence on neurons during MS remains unsolved. The aim of this study is to assess the effect of weaker signaling through hCX3CR^1I249/M280 during EAE. We hypothesize that dysregulated microglial responses due to impaired CX3CR1 signaling enhance neuronal/axonal damage. We generated an animal model replacing the mouse CX3CR1 locus for the hCX3CR^1I249/M280 variant. Upon EAE induction, these mice exhibited exacerbated EAE correlating with severe inflammation and neuronal loss. We also observed that mice with aberrant CX3CR1 signaling are unable to produce FKN and ciliary neurotrophic factor during EAE in contrast to wild type mice. Our results provide validation of defective function of the hCX3CR^1I249/M280 variant and the foundation to broaden the understanding of microglia dysfunction during neuroinflammation.

Original Citation

Cardona, S. M., Kim, S. V., Church, K. A., Torres, V. O., Cleary, I. A., Mendiola, A. S., Saville, S. P., Watowich, S. S., Parker-Thornburg, J., Soto-Ospina, A., Araque, P., Ransohoff, R. M., & Cardona, A. E. (2018). Role of the Fractalkine Receptor in CNS Autoimmune Inflammation: New Approach Utilizing a Mouse Model Expressing the Human CX3CR1I249/M280 Variant. Frontiers in Cellular Neuroscience, 12. https://doi.org/10.3389/fncel.2018.00365

ScholarWorks Citation

Cardona, Sandra M.; Kim, Sangwon V.; Church, Kaira A.; Torres, Vanessa O.; Cleary, Ian A.; Mendiola, Andrew S.; Saville, Stephen P.; Watowich, Stephanie S.; Parker-Thornburg, Jan; Soto-Ospina, Alejandro; Ransohoff, Richard M.; and Cardona, Astrid E., "Role of the Fractalkine Receptor in CNS Autoimmune Inflammation: New Approach Utilizing a Mouse Model Expressing the Human CX3CR1^I249/M280 Variant" (2018). Peer Reviewed Articles. 57.
https://scholarworks.gvsu.edu/bms_articles/57