The transmembrane chemokine fractalkine (CX3CL1) present on neurons and peripheral endothelial cells acts as an adhesion molecule or as a soluble chemoattractant. CX3CL1 signals through its receptor CX3CR1 which is expressed in microglia, monocytes/macrophages and dendritic cells, NK cells and T cells. Notably, multiple sclerosis patients revealed lower expression of CX3CR1 in peripheral NK cells when compared to healthy controls and lack of CX3CR1+ cells in peripheral blood correlated with disease activity. However, the role of CX3CR1 in antigen presenting cells and T cells, and their contribution to CNS pathology are still enigmatic. The hypothesis behind the proposed research is that CX3CR1/CX3CL1 regulates antigen presenting cell (APC) effector functions influencing the development of pathogenic T cells during experimental autoimmune encephalomyelitis (EAE). This hypothesis is based on the following: 1) EAE symptoms are more severe and CNS demyelination is enhanced CX3CR1-deficient mice, 2) absence of CX3CR1 correlated with a selective accumulation of CD115+CD11c+ dendritic cells to CNS tissues, and 3) Bone marrow chimeric mice revealed that absence of CX3CR1 in bone marrow induced an unusual, severe and chronic non-remitting EAE disease with sustained paralysis. The overall goal of this proposal is to elucidate the function of CX3CR1 during EAE and how it regulates pathogenic CNS inflammation.
The specific aims are: 1. to determine the role of CX3CR1 for the initiation of EAE via modulation of antigen presentation and T cell priming. We will test the hypothesis that CX3CR1 controls peripherally DC maturation affecting antigen presentation and subsequently peripheral T cell polarization. We will investigate the role of CX3CR1 antigen trafficking and dendritic cell mobilization and effects of CX3CR1-deficiency in generation of encephalitogenic T cells. 2. To determine the role of CX3CR1 deficiency in the effector phase of EAE and protection from neuronal damage and demyelination. We hypothesize that absence of CX3CR1 in bone marrow is critical for the maintenance of T cell mediated inflammation and tissue damage in the EAE brain. We will investigate the role of CX3CR1 in inhibitory signaling, activation, and survival of pathogenic and regulatory T cell subsets within CNS tissues at peak of disease and at time of recovery. 3. To define address how weaker signaling through human CX3CR1I249/M280 replicates the pathology of Cx3cr1-/- mice during EAE. We hypothesize that I249/M280 expressing cells will exhibit effector functions comparable to CX3CR1-deficient cells. We will use knock-in mice expressing the human variant as a low affinity model to investigate the role of the I249/M280 in APC activation and T cell polarization in vivo during CNS autoimmunity.

Public Health Relevance

More than 20% of the population carries a variant fractalkine receptor (CX3CR1) with defective functions. This research will address the role of CX3CR1 during the immune response associated with experimental autoimmune encephalomyelitis as a model of multiple sclerosis (MS). Defining the beneficial or detrimental effects of CX3CR1 will advance prevention and treatment strategies for patients living with MS.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Enhancement Award (SC1)
Project #
1SC1GM095426-01A1
Application #
8213930
Study Section
Special Emphasis Panel (ZGM1-MBRS-9 (SC))
Program Officer
Dunsmore, Sarah
Project Start
2012-02-03
Project End
2016-11-30
Budget Start
2012-02-03
Budget End
2012-11-30
Support Year
1
Fiscal Year
2012
Total Cost
$294,000
Indirect Cost
$94,000
Name
University of Texas Health Science Center San Antonio
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
800189185
City
San Antonio
State
TX
Country
United States
Zip Code
78249
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Cardona, Sandra M; Kim, Sangwon V; Church, Kaira A et al. (2018) Role of the Fractalkine Receptor in CNS Autoimmune Inflammation: New Approach Utilizing a Mouse Model Expressing the Human CX3CR1I249/M280 Variant. Front Cell Neurosci 12:365
Rhodes, Christopher T; Zunino, Giulia; Huang, Shu-Wei Angela et al. (2018) Region specific knock-out reveals distinct roles of chromatin modifiers in adult neurogenic niches. Cell Cycle 17:377-389
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Solano Fonseca, Rene; Mahesula, Swetha; Apple, Deana M et al. (2016) Neurogenic Niche Microglia Undergo Positional Remodeling and Progressive Activation Contributing to Age-Associated Reductions in Neurogenesis. Stem Cells Dev 25:542-55
Hertwig, Laura; Hamann, Isabell; Romero-Suarez, Silvina et al. (2016) CX3CR1-dependent recruitment of mature NK cells into the central nervous system contributes to control autoimmune neuroinflammation. Eur J Immunol 46:1984-96
Maphis, Nicole; Xu, Guixiang; Kokiko-Cochran, Olga N et al. (2015) Loss of tau rescues inflammation-mediated neurodegeneration. Front Neurosci 9:196
Maphis, Nicole; Xu, Guixiang; Kokiko-Cochran, Olga N et al. (2015) Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain. Brain 138:1738-55
Cardona, Sandra M; Mendiola, Andrew S; Yang, Ya-Chin et al. (2015) Disruption of Fractalkine Signaling Leads to Microglial Activation and Neuronal Damage in the Diabetic Retina. ASN Neuro 7:
Febinger, Heidi Y; Thomasy, Hannah E; Pavlova, Maria N et al. (2015) Time-dependent effects of CX3CR1 in a mouse model of mild traumatic brain injury. J Neuroinflammation 12:154

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