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PMID:25690660

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Citation

Kobayashi, M, Konishi, H, Takai, T and Kiyama, H (2015) A DAP12-dependent signal promotes pro-inflammatory polarization in microglia following nerve injury and exacerbates degeneration of injured neurons. Glia 63:1073-82

Abstract

Under pathological conditions, activated microglia play paradoxical roles and could have neurotoxic or neuroprotective effects. However, the signal determining how activated microglia affects the fate of neuronal cells remains largely unknown. Here we demonstrate that DNAX-activating protein of 12 kDa (DAP12), a transmembrane adaptor protein that contains an immunoreceptor tyrosine-based activation motif, is a critical regulator of microglial function after nerve injury. In a model of mouse hypoglossal nerve injury, the duration of microglial increase after nerve injury became shorter in mice lacking DAP12, although microglial morphology and total cell numbers were not significantly affected during early phase after nerve injury. Intriguingly, expressions of M1-phenotype markers including pro-inflammatory cytokines were suppressed in DAP12-deficient microglia. Furthermore, axotomy-induced motor neuron death was markedly prevented in DAP12-deficient mice. Collectively, DAP12-mediated microglial activation following axotomy promotes pro-inflammatory responses, and thereby accelerates nerve injury-induced neuron death, suggesting that DAP12 is a potential therapeutic target for the protection of neuronal degeneration caused by microglial activation.

Links

PubMed Online version:10.1002/glia.22802

Keywords

Adaptor Proteins, Signal Transducing/genetics; Adaptor Proteins, Signal Transducing/metabolism; Animals; Cell Count; Cell Death/physiology; Cells, Cultured; Cytokines/metabolism; Disease Models, Animal; Hypoglossal Nerve Injuries/pathology; Hypoglossal Nerve Injuries/physiopathology; Lipopolysaccharides/toxicity; Male; Mice, Inbred C57BL; Mice, Knockout; Microglia/pathology; Microglia/physiology; Motor Neurons/pathology; Motor Neurons/physiology; Nerve Degeneration/pathology; Nerve Degeneration/physiopathology; Time Factors

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:TYOBP

involved_in

GO:0032760: positive regulation of tumor necrosis factor production

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:TYOBP

involved_in

GO:0032755: positive regulation of interleukin-6 production

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:TYOBP

involved_in

GO:0032731: positive regulation of interleukin-1 beta production

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:TYOBP

involved_in

GO:0032693: negative regulation of interleukin-10 production

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(CL:0000129)

Seeded From UniProt

complete

MOUSE:TYOBP

involved_in

GO:0010628: positive regulation of gene expression

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • part_of:(GO:0048678)
  • occurs_in:(CL:0000129)
  • part_of:(GO:0002282)
  • regulates_expression_of:(UniProtKB:P42082)

Seeded From UniProt

complete

MOUSE:TYOBP

involved_in

GO:0010628: positive regulation of gene expression

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • part_of:(GO:0048678)
  • occurs_in:(CL:0000129)
  • part_of:(GO:0002282)
  • regulates_expression_of:(UniProtKB:P31996)

Seeded From UniProt

complete

MOUSE:TYOBP

involved_in

GO:0002282: microglial cell activation involved in immune response

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:TYOBP

involved_in

GO:0048678: response to axon injury

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(CL:0000129)
  • has_agent:(UBERON:0001650)

Seeded From UniProt

complete

MOUSE:TYOBP

involved_in

GO:0002282: microglial cell activation involved in immune response

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:TYOBP

involved_in

GO:0042535: positive regulation of tumor necrosis factor biosynthetic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:TYOBP

involved_in

GO:0050725: positive regulation of interleukin-1 beta biosynthetic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:TYOBP

involved_in

GO:0045410: positive regulation of interleukin-6 biosynthetic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:TYOBP

involved_in

GO:0010628: positive regulation of gene expression

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • part_of:(GO:0048678)
  • occurs_in:(CL:0000129)
  • part_of:(GO:0002282)
  • regulates_expression_of:(ENSEMBL:ENSMUSG00000018774)

Seeded From UniProt

complete

MOUSE:TYOBP

involved_in

GO:0010628: positive regulation of gene expression

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • part_of:(GO:0048678)
  • occurs_in:(CL:0000129)
  • part_of:(GO:0002282)
  • regulates_expression_of:(ENSEMBL:ENSMUSG00000022901)

Seeded From UniProt

complete

MOUSE:TYOBP

involved_in

GO:0045081: negative regulation of interleukin-10 biosynthetic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

occurs_in:(CL:0000129)

Seeded From UniProt

complete

MOUSE:TYOBP

involved_in

GO:0032911: negative regulation of transforming growth factor beta1 production

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:TYOBP

involved_in

GO:1901216: positive regulation of neuron death

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • part_of:(GO:0048678)
  • occurs_in:(CL:0000129)
  • regulates_o_occurs_in:(UBERON:0001650)
  • part_of:(GO:0002282)
  • regulates_o_occurs_in:(CL:0000540)

Seeded From UniProt

complete

Notes

See also

References

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