Toll/interleukin-1 receptor domain-containing adapter inducing interferon-β mediates microglial phagocytosis of degenerating axons

Suneil Hosmane, Million Adane Tegenge, Labchan Rajbhandari, Prech Uapinyoying, Nishant Ganesh Kumar, Nitish V Thakor, Arun Venkatesan

Research output: Contribution to journalArticle

Abstract

Following CNS injury, microglial phagocytosis of damaged endogenous tissue is thought to play an important role in recovery and regeneration. Previous work has focused on delineating mechanisms of clearance of neurons and myelin. Little, however, is known of the mechanisms underlying phagocytosis of axon debris. We have developed a novel microfluidic platform that enables coculture of microglia with bundles of CNS axons to investigate mechanisms of microglial phagocytosis of axons. Using this platform, we find that axon degeneration results in the induction of type-1 interferon genes within microglia. Pharmacologic and genetic disruption of Toll/ interleukin-1 receptor domain-containing adapter inducing interferon-β (TRIF), a Toll-like receptor adapter protein, blocks induction of the interferon response and inhibits microglial phagocytosis of axon debris in vitro. In vivo, microglial phagocytosis of axons following dorsal root axotomy is impaired in mice in which TRIF has been genetically deleted. Furthermore, we identify the p38 mitogen-activated protein kinase (MAPK) cascade as a signaling pathway downstream of TRIF following axon degeneration and find that inhibition of p38 MAPKby SB203580 (4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole) also blocked clearance of axon debris. Finally, we find that TRIF-dependent microglial clearance of unmyelinated axon debris facilitates axon outgrowth. Overall, we provide evidence that TRIF-mediated signaling plays an unexpected role in axonal debris clearance by microglia, thereby facilitating a more permissive environment for axonal outgrowth. Our study has significant implications for the development of novel regenerative and restorative strategies for the many traumatic, neuro inflammatory, and neurodegenerative conditions characterized by CNS axon degeneration.

Original languageEnglish (US)
Pages (from-to)7745-7757
Number of pages13
JournalJournal of Neuroscience
Volume32
Issue number22
DOIs
Publication statusPublished - May 30 2012

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ASJC Scopus subject areas

  • Neuroscience(all)

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