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

## TL;DR

The immunoproteasome in microglia plays a key role in regulating innate immune responses, including phagocytosis and cytokine production.

## Contribution

This study reveals novel functions of the immunoproteasome in innate immunity and identifies NADH as a potential inhibitor.

## Key findings

- Immunoproteasome inhibition reduces IFNγ-dependent C1q induction and suppresses phagocytosis in microglia.
- The immunoproteasome regulates IκBα degradation, affecting NF-κB signaling.
- NADH prevents immunoproteasome induction, offering a pathway to suppress immune responses.

## Abstract

Microglia are the resident immune cells of the central nervous system (CNS). We and others have shown that the inflammatory response of microglia is partially regulated by the immunoproteasome, an inducible form of the proteasome responsible for the generation of major histocompatibility complex (MHC) class I epitopes. While the role of the proteasome in the adaptive immune system is well established, emerging evidence suggests the immunoproteasome may have discrete functions in the innate immune response. Here, we show that inhibiting the immunoproteasome reduces the IFNγ-dependent induction of complement activator C1q, suppresses phagocytosis, and alters the cytokine expression profile in a microglial cell line (BV2) and microglia derived from human inducible pluripotent stem cells. Moreover, we show that the immunoproteasome regulates the degradation of IκBα, a modulator of NF-κB signaling. Finally, we demonstrate that NADH prevents induction of the immunoproteasome, representing a potential pathway to suppress immunoproteasome-dependent immune responses.

The online version contains supplementary material available at 10.1038/s41598-025-25341-5.