Neuroinflammation is a key central nervous system (CNS) response that protects the brain following injury, trauma, and infection; however, chronic neuroinflammation is recognized as a pathologic manifestation of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease (PD), and Multiple Sclerosis. The inflammatory process is well characterized in cells of the immune system but less is known about how CNS cells can initiate inflammation. Neurons and glia are resident cells in the CNS that have been reported to secrete pro-inflammatory cytokines. Among CNS cells, astrocytes have emerged as mediators of inflammation resulting from infection and injury where they release various chemokines and cytokines important in recruiting and activating peripheral immune cells. This creates an important interface in which astrocytes detecting pathologies initiated within the CNS can then in turn modulate the progression of inflammation in both the CNS and potentially in the systemic immune system. Ongoing studies in our laboratory indicate that mice ingesting the disease-associated metabolic neurotoxin rotenone have elevated levels of the pro-inflammatory cytokines including interleukin 6 (IL6) observable in brain extracts. IL6 is an important inflammatory mediator whose levels are elevated in association with multiple neurodegenerative disorders. Astrocytes have been reported to secrete IL6 in response to tumor necrosis factor (TNF) and interleukin 1b (IL1b); however, we do not yet know whether astrocytes are the cellular origin of IL6 observed following rotenone exposure. The JAK/STAT signal transduction pathway is activated by IL6 and was recently reported to comprise a feed-forward autocrine loop in glial tumor cells. If such a mechanism existed in pro-inflammatory astrocytes it would be of great interest since self-perpetuating neuroinflammation is posited to contribute to normal aging and the progression of chronic neurologic disorders of the elderly. A major component of the training program will be the execution of molecular biology studies to test the prediction that astrocytes are the cellular origin of IL6 induced by disease- associated neurotoxin exposure in primary cultures. In these studies, we will determine if the JAK/STAT signal transduction pathway is activated by neurotoxins, and if once established, this pathway can be sustained in an IL6-dependent manner following cessation of exposure. In our second aim, we will use histologic and biochemical techniques to determine if the IL6/JAK/STAT pathway is activated and sustained in mice initially exposed to the disease-associated pesticide rotenone and determine if treatment with a pharmacologic inhibitor of JAK/STAT can normalize IL6 levels in mice during and following rotenone exposure. Understanding the basic cellular and molecular mechanisms of IL6 induction in astrocytes and in CNS cells subjected to neurotoxic stress may identify new pathways of interest for detecting and treating neuroinflammation occurring in association with normal aging and disease.

Public Health Relevance

Chronic neuroinflammation is associated with the progression of multiple neurologic disorders. We propose to characterize IL6 secretion in brain cells, a pathway that when activated may contribute to prolonged self- sustaining neuroinflammation. These experiments will lead to a deeper understanding of the molecular basis of cytokine secretion in the central nervous system in the context of deleterious long-term neuroinflammation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31NS098630-02
Application #
9502858
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Sieber, Beth-Anne
Project Start
2017-04-01
Project End
2020-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Dartmouth College
Department
Type
Graduate Schools
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755