Fyn kinase regulates microglial neuroinflammatory responses in cell culture and animal models of parkinson’s disease

Nikhil Panicker, Hariharan Saminathan, Huajun Jin, Matthew Neal, Dilshan S. Harischandra, Richard Gordon, Kavin Kanthasamy, Vivek Lawana, Souvarish Sarkar, Jie Luo, Vellareddy Anantharam, Anumantha G. Kanthasamy, Arthi Kanthasamy

Research output: Contribution to journalArticlepeer-review

Abstract

Sustained neuroinflammation mediated by resident microglia is recognized as a key pathophysiological contributor to many neurodegenerative diseases, including Parkinson’s disease (PD), but the key molecular signaling events regulating persistent microglial activation have yet to be clearly defined. In the present study, we examined the role of Fyn, a non-receptor tyrosine kinase, in microglial activation and neuroinflammatory mechanisms in cell culture and animal models of PD. The well-characterized inflammogens LPS and TNFɑ rapidly activated Fyn kinase in microglia. Immunocytochemical studies revealed that activated Fyn preferentially localized to the microglial plasma membrane periphery and the nucleus. Furthermore, activated Fyn phosphorylated PKCδ at tyrosine residue 311, contributing to an inflammogen-induced increase in its kinase activity. Notably, the Fyn-PKCδ signaling axis further activated the LPSand TNFɑ-induced MAP kinase phosphorylation and activation of the NFkB pathway, implying that Fyn is a major upstream regulator of proinflammatory signaling. Functional studies in microglia isolated from wild-type (Fyn+/+) and Fyn knock-out (Fyn-/-) mice revealed that Fyn is required for proinflammatory responses, including cytokine release as well as iNOS activation. Interestingly, a prolonged inflammatory insult induced Fyn transcript and protein expression, indicating that Fyn is upregulated during chronic inflammatory conditions. Importantly, in vivo studies using MPTP, LPS, or 6-OHDA models revealed a greater attenuation of neuroinflammatory responses in Fyn-/- and PKCδ-/- mice compared with wild-type mice. Collectively, our data demonstrate that Fyn is a major upstream signaling mediator of microglial neuroinflammatory processes in PD.

Original languageEnglish (US)
Pages (from-to)10058-10077
Number of pages20
JournalJournal of Neuroscience
Volume35
Issue number27
DOIs
StatePublished - Jul 8 2015
Externally publishedYes

Keywords

  • Fyn
  • Kinase
  • Microglia
  • Neuroinflammation
  • Parkinson’s disease
  • Phosphorylation

ASJC Scopus subject areas

  • Neuroscience(all)

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