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LAG-3 expression in microglia regulated by IFN-γ/STAT1 pathway and metalloproteases

Yuta Morisaki1, Motoki Ohshima1, Hikaru Suzuki1

  • 1Division of Pharmacology, Faculty of Pharmacy, Keio University, Tokyo, Japan.

Frontiers in Cellular Neuroscience
|November 29, 2023
PubMed

Insights

Lymphocyte activation gene-3 (LAG-3) expression in microglia is induced by interferon-gamma (IFN-γ) via the STAT1 pathway. This immune checkpoint molecule

Area of Science:

  • Neuroimmunology
  • Innate Immunity
  • Central Nervous System (CNS) Homeostasis

Background:

  • Microglia, the resident immune cells of the CNS, are crucial for maintaining brain homeostasis.
  • Dysregulated microglial activation contributes to neurotoxicity in various CNS disorders.
  • Mechanisms governing microglial activation, particularly involving immune checkpoint molecules, remain incompletely understood.

Purpose of the Study:

  • To investigate the expression mechanisms of immune checkpoint molecules in activated microglia.
  • To elucidate the role of interferon-gamma (IFN-γ) and the STAT1 pathway in regulating microglial immune checkpoint expression.
  • To characterize the regulation of lymphocyte activation gene-3 (LAG-3) in microglia.

Main Methods:

  • Analysis of immune checkpoint molecule expression in BV2 microglial cell line and primary microglia.
  • Utilized siRNA targeting STAT1 to investigate IFN-γ-induced LAG-3 expression.
  • Assessed the impact of metalloproteinase inhibitors (ADAM10, ADAM17) on soluble LAG-3 production.
  • Administered IFN-γ into the cisterna magna of mice to evaluate in vivo LAG-3 expression in spinal microglia.
  • Investigated the effect of LAG-3 knockdown on nitric oxide production in IFN-γ-activated microglia.

Main Results:

  • IFN-γ stimulation upregulated both membrane-bound and soluble forms of lymphocyte activation gene-3 (LAG-3) in microglia.
  • IFN-γ-induced LAG-3 expression was dependent on the STAT1 signaling pathway.
  • Soluble LAG-3 production was mediated by metalloproteinases, including ADAM10 and ADAM17.
  • In vivo IFN-γ administration increased LAG-3 expression in spinal microglia.
  • LAG-3 knockdown enhanced nitric oxide production in IFN-γ-activated microglia.

Conclusions:

  • Microglial LAG-3 expression is primarily induced by the IFN-γ-STAT1 signaling axis.
  • Soluble LAG-3 is generated through the proteolytic cleavage of membrane-bound LAG-3 by metalloproteinases.
  • LAG-3 negatively regulates microglial pro-inflammatory responses, such as nitric oxide production.
Keywords:
ADAMIFN-γLAG-3immune checkpoint moleculemicroglia

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