Fyn kinase regulates microglial neuroinflammatory responses in cell culture and animal models of Parkinson’s disease (1055.7)

Abstract

Sustained neuroinflammation is recognized as a key pathophysiological contributor to many neurodegenerative diseases, including Parkinson’s disease (PD). Resident brain microglia mediate chronic neuroinflammation through the production of proinflammatory cytokines and chemokines. Identifying the key molecular signaling events perpetuating microglial activation could unravel novel mechanisms underlying glial‐neuronal interactions that contribute to persistent inflammation and progressive neurodegeneration in PD. In the present study, we examined the role that Fyn, a non‐receptor tyrosine kinase, plays in microglial activation in cell culture and animal models of PD. First, we show that the known inflammogen LPS (lipopolysaccharide) rapidly activated Fyn kinase, as measured by Fyn‐Y416 phosphorylation and Fyn kinase assays in the BV2 microglial cell line as well as in primary microglia. Notably, immunocytochemical studies revealed that activated Fyn is preferentially localized to the microglial membrane periphery. Furthermore, stimulation of microglia with LPS induced phosphorylation of PKCδ at tyrosine 311. PKCδ Y311 phosphorylation was diminished in Fyn Knockout (Fyn KO) microglia, indicating that Fyn mediates this event. Functional studies revealed that the LPS‐induced production of cytokines, chemokines and nitrite were significantly attenuated in microglia isolated from Fyn KO and PKCδ KO primary microglia, when compared to wild type microglia. Furthermore, Fyn was found to be essential for LPS‐induced MAP kinase phosphorylation and activation of the NFκB pathway. Next, we extended our studies to LPS and MPTP‐induced animal models of neuroinflammation. We observed attenuated microglial proliferation and reduced production of the striatal TNFα, IL‐6 and IL‐12 in Fyn knockout mice. Collectively, these findings suggest that Fyn‐PKCδ signaling plays a critical role in mediating neuroinflammatory responses in PDGrant Funding Source: Supported by NIH grants NS65167 and NS078247