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Key features of the innate immune response is mediated by the immunoproteasome in microglia

Salman Izadjoo1, Kasey E Moritz2,3, Guzal Khayrullina2

  • 1Molecular and Cell Biology Program, Uniformed Services University, F. Edward Hebert School of Medicine, Bethesda, MD, USA.

Scientific Reports
|November 21, 2025
PubMed

Insights

The immunoproteasome regulates microglial immune responses, including phagocytosis and cytokine profiles. NADH can suppress these responses by preventing immunoproteasome induction, offering a potential therapeutic avenue.

Area of Science:

  • Neuroimmunology
  • Cellular Biology
  • Innate Immunity

Background:

  • Microglia are central nervous system immune cells.
  • The immunoproteasome regulates MHC class I epitope generation and is implicated in adaptive immunity.
  • Emerging evidence suggests distinct roles for the immunoproteasome in innate immune responses.

Purpose of the Study:

  • To investigate the role of the immunoproteasome in microglial innate immune functions.
  • To explore the regulatory mechanisms of the immunoproteasome in microglia.
  • To identify potential pathways for modulating immunoproteasome activity.

Main Methods:

  • Utilized a microglial cell line (BV2) and human induced pluripotent stem cell-derived microglia.
  • Inhibited the immunoproteasome to assess its impact on microglial functions.
  • Analyzed complement activator C1q induction, phagocytosis, cytokine profiles, IκBα degradation, and NF-κB signaling.
  • Investigated the effect of NADH on immunoproteasome induction.

Main Results:

  • Immunoproteasome inhibition reduced IFNγ-dependent C1q induction and suppressed phagocytosis.
  • Altered cytokine expression profiles were observed in microglia upon immunoproteasome inhibition.
  • The immunoproteasome was shown to regulate IκBα degradation, a key step in NF-κB signaling.
  • NADH was found to prevent the induction of the immunoproteasome.

Conclusions:

  • The immunoproteasome plays a significant role in regulating microglial innate immune responses.
  • Targeting the immunoproteasome, potentially via NADH, offers a strategy to suppress microglial immune activation.
Keywords:
ComplementCytokinesImmunoproteasomeInnate immunityMicrogliaNFκ-BONX-0914Phagocytosis

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