NK cells in CNS inflammation and autoimmunity Project Summary: Natural killer (NK) cells are large, granular lymphocytes that operate through cytolytic activity and cytokine secretion, and represent an important component of the innate immune system. Our group has long been interested in understanding the biological functions of NK cells in autoimmune diseases, particularly their role in inflammation and autoimmunity in the central nervous system (CNS) such as multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). Preliminary data and relevant literature suggest that the initiation of MS/EAE may stem from the interplay between cells of the innate and adaptive immune systems, including NK cells. To test this possibility, we developed several cellular and genetic approaches to manipulate NK cells systemically and in the CNS, and investigated the capacity of these cells to impact the magnitude of CNS inflammation and autoimmunity to myelin antigens. We demonstrated that the systemic depletion of NK cells in all organ system using an anti-NK1.1 mAb, or selectively reduced the homing of NK cells to the CNS through a germ-line deletion of the chemokine receptor CX3CR1, leads to pronounced mononuclear lymphocyitic infiltration into the CNS, demyelination, and preferential expansion of CNS myelin- reactive Th17. Conversely, the expansion of NK cells via the engagement of the IL-2 receptor on NK cells significantly attenuated the CNS, but not peripheral Th17 cell responses. Further investigations revealed that NK cells reside in proximity to microglia in the CNS, and that can kill microglia. When NK cells were depleted or were unable to home to the CNS, microglia expanded and produced large amounts of Th17 polarizing cytokines. Also, the absence of NK cells promoted the activation of the Th17 lineage-specific transcription factors Rorc and STAT3 in a manner that was dependent on microglia. Based on these preliminary studies, we propose to dissect the cellular mechanism governing NK cell-mediated protection from EAE. Our central hypothesis is that NK cells control microglia in the inflamed CNS, and that NK cell/microglia interactions can inhibit myelin-reactive Th-17 cells and protect against CNS autoimmunity. To test this hypothesis, we will: 1) Dissect the interactions between NK cells and microglia in the CNS and identify the mechanism responsible for the cytolytic activity of NK cells against microglia;2) Define the impact of NK cell/microglia interactions on the generation, maintenance and function of myelin-reactive CD4+ Th17 cells in the CNS;3) Test NK-based therapeutic approaches for the protection from CNS inflammation and autoimmunity.

Public Health Relevance

NK cells in CNS inflammation and autoimmunity Project Narrative: This study will elucidate key mechanisms by which natural killer (NK) cells can inhibit inflammation and autoimmunity in the central nervous system (CNS). The feasibility of NK-based therapeutic intervention in preventing CNS inflammation will be explored and the outcomes evaluated for possible implementation in the design of novel treatments for CNS inflammation and autoimmunity.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01AI083294-05
Application #
8640875
Study Section
Innate Immunity and Inflammation (III)
Program Officer
Esch, Thomas R
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
St. Joseph's Hospital and Medical Center
Department
Type
DUNS #
City
Phoenix
State
AZ
Country
United States
Zip Code
85013
Yan, Yaping; Li, Yujing; Fu, Ying et al. (2016) Autoantibody to MOG suggests two distinct clinical subtypes of NMOSD. Sci China Life Sci 59:1270-1281
Fu, Ying; Liu, Qiang; Anrather, Josef et al. (2015) Immune interventions in stroke. Nat Rev Neurol 11:524-35
Pan, Jing; Zhao, Peng; Cai, Hao et al. (2015) Hypoxemia, Sleep Disturbances, and Depression Correlated with Fatigue in Neuromyelitis Optica Spectrum Disorder. CNS Neurosci Ther 21:599-606
Zhu, Zilong; Fu, Ying; Tian, Decai et al. (2015) Combination of the Immune Modulator Fingolimod With Alteplase in Acute Ischemic Stroke: A Pilot Trial. Circulation 132:1104-12
Fu, Ying; Zhang, Ningnannan; Ren, Li et al. (2014) Impact of an immune modulator fingolimod on acute ischemic stroke. Proc Natl Acad Sci U S A 111:18315-20
Su, Ning; Shi, Samuel X; Zhu, Xiaodong et al. (2014) Interleukin-7 expression and its effect on natural killer cells in patients with multiple sclerosis. J Neuroimmunol 276:180-6
Gan, Yan; Liu, Qiang; Wu, Wei et al. (2014) Ischemic neurons recruit natural killer cells that accelerate brain infarction. Proc Natl Acad Sci U S A 111:2704-9
Sun, Feng; Ladha, Shafeeq S; Yang, Li et al. (2014) Interleukin-10 producing-B cells and their association with responsiveness to rituximab in myasthenia gravis. Muscle Nerve 49:487-94
Zhang, Cun-Jin; Zhai, Hui; Yan, Yaping et al. (2014) Glatiramer acetate ameliorates experimental autoimmune neuritis. Immunol Cell Biol 92:164-9
Fu, Ying; Hao, Junwei; Zhang, Ningnannan et al. (2014) Fingolimod for the treatment of intracerebral hemorrhage: a 2-arm proof-of-concept study. JAMA Neurol 71:1092-101

Showing the most recent 10 out of 33 publications