Inflammasome function in neuroinflammation:a role for microglia in Parkinson’s disease

SCHEME: CORE

CALL: 2011

DOMAIN: BM - Translational Biomedical Research

FIRST NAME: Catherine

LAST NAME: Dostert

INDUSTRY PARTNERSHIP / PPP: No

INDUSTRY / PPP PARTNER:

HOST INSTITUTION: University of Luxembourg

KEYWORDS: Inflammasome, IL-1beta, microglia, Parkinson's disease, neurodegeneration, mitochondria

START: 2012-06-01

END: 2015-05-31

WEBSITE: https://www.uni.lu

Submitted Abstract

Neuroinflammation is the local reaction of the brain to infection, trauma, toxic molecules or protein aggregates. The brain resident macrophages, microglia, are the first line of defense in this relatively sensitive organ and are able to trigger an appropriate response involving secretion of cytokines and chemokines as well as the recruitment of peripheral immune cells (Rivest, 2009). IL-1ß plays an important role in this response and its implication in neurodegenerative diseases needs further characterization. IL-1ß is a potent pyrogen whose production is induced by the activation of the innate immune system. Dysregulated production of this cytokine can give rise to inflammatory diseases. Although IL-1ß has been known for a long time to be active only when processed by caspase-1, the molecular mechanisms leading to this cleavage have only been recently discovered and take place in a molecular complex termed the inflammasome (Martinon et al., 2002). Gain-of-function mutations in the NACHT domain of NLRP3, resulting in a constitutively active protein, are involved in autoinflammatory disorders, the cryopyrin-associated periodic syndromes (CAPS) (Stojanov and Kastner, 2005). Patients have spontaneous processing and secretion of IL-1ß, which can be reduced by administration of the IL-1ß receptor antagonist IL-1RA (Anakinra) (Goldbach-Mansky et al., 2006). We propose to study inflammasome activation and function in the brain, especially in microglial cells. To further characterize the importance of the inflammasome in neurodegenerative diseases, in particular Parkinson’s Disease, animal models will be of great importance. A systems biology approach will be established in this project together with the LCSB, as well as a metabolome analysis of inflammasome activation. The readily available IL-1ß receptor antagonist rIL-1RA (Anakinra) and anti-IL-1ß antibodies that are used to treat CAPS patients could allow the rapid translation of fundamental in vitro and in vivo findings to the clinic. Studying the IL-1 system in the brain may not only improve our understanding of inflammatory mechanisms in neurodegeneration, but also serve as a basis for designing effective therapies.

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