We hypothesize that the anti-inflammatory cytokines IL-13 and IL-4 play an important role in the death of dopaminergic neurons in the Substantia nigra pars compacta (SNc), the same cells that are lost in human Parkinson's disease (PD). This hypothesis is based on our preliminary studies in mice which showed that interleukin 13 receptor alpha 1 chain (IL-13R?1), is highly expressed in DA neurons in the SNc and that mice that are deficient is this receptor are protected from the loss of dopaminergic (DA) neurons that occurs during chronic peripheral injection with low doses of LPS. Furthermore, in vitro studies using a dopaminergic cell line showed that while IL-13 alone does not have harmful effects on DA neurons, it strongly potentiates the toxicity of mild oxidative stress. Similar results were obtained with IL-4, another cytokine capable of activating IL- 13R?1-dependent signaling. Together these results suggest a novel mechanism whereby anti-inflammatory cytokines can contribute to neuronal loss under conditions of stress. We propose to investigate our hypothesis in three specific aims. In SA1, we will determine how the interaction between IL-13 (and IL-4) signaling and oxidative stress induces neuronal damage in vitro. In SA2, we will investigate the contribution of each of these cytokines to neuronal loss in vivo in a model of neuro-inflammation. In SA3, we will determine the cellular source of IL-13 and IL-4 during inflammation. These studies are highly relevant to understanding the role of inflammation in the pathogenesis of PD and may identify novel therapeutic targets for the treatment of this disease.

Public Health Relevance

We propose to investigate the role of two cytokine signaling molecules, interleukins 13 and 4, in the survival of dopaminergic neurons in the brain during neuro-inflammation. The results are highly relevant to understanding the pathophysiology of Parkinson's Disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Sieber, Beth-Anne
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Scripps Research Institute
La Jolla
United States
Zip Code
Sugama, Shuei; Sekiyama, Kazunari; Kodama, Tohru et al. (2016) Chronic restraint stress triggers dopaminergic and noradrenergic neurodegeneration: Possible role of chronic stress in the onset of Parkinson's disease. Brain Behav Immun 51:39-46
Mori, Simone; Maher, Pamela; Conti, Bruno (2016) Neuroimmunology of the Interleukins 13 and 4. Brain Sci 6:
Sanchez-Alavez, Manuel; Nguyen, William; Mori, Simone et al. (2015) Monoacylglycerol Lipase Regulates Fever Response. PLoS One 10:e0134437
Marcondes, Maria Cecilia Garibaldi; Ojakian, Ryan; Bortell, Nikki et al. (2014) Osteopontin expression in the brain triggers localized inflammation and cell death when immune cells are activated by pertussis toxin. Mediators Inflamm 2014:358218