The role of the immunoproteasome in interferon-γ-mediated microglial activation

Abstract

Microglia regulate the brain microenvironment by sensing damage and neutralizing potentially harmful insults. Disruption of central nervous system (CNS) homeostasis results in transition of microglia to a reactive state characterized by morphological changes and production of cytokines to prevent further damage to CNS tissue. Immunoproteasome levels are elevated in activated microglia in models of stroke, infection and traumatic brain injury, though the exact role of the immunoproteasome in neuropathology remains poorly defined. Using gene expression analysis and native gel electrophoresis we characterize the expression and assembly of the immunoproteasome in microglia following interferon-gamma exposure. Transcriptome analysis suggests that the immunoproteasome regulates multiple features of microglial activation including nitric oxide production and phagocytosis. We show that inhibiting the immunoproteasome attenuates expression of pro-inflammatory cytokines and suppresses interferon-gamma-dependent priming of microglia. These results imply that targeting immunoproteasome function following CNS injury may attenuate select microglial activity to improve the pathophysiology of neurodegenerative conditions or the progress of inflammation-mediated secondary injury following neurotrauma.

A Sentinel in the Crosstalk Between the Nervous and Immune System: The (Immuno)-Proteasome

“…These results confirm that IP induction follows neuro-inflammation, which develops during protein aggregation. This is reproduced in experimental models of AD (117), ALS (134, 140), neurotrauma (129), ischemic stroke (104), epilepsy (100, 127), and MS (101), where the onset of inflammation accelerates IP expression and neuropathology. In neurodegenerative disorders, overlapping molecular mechanisms operate to foster neuro-inflammation and IP induction in either neurons or glia.…”

“…In neurons and glial cells, IP is generally induced by the pro-inflammatory cytokines IFNγ and TNFα, and by oxidative stress (42, 80, 82, 128). In these challenging conditions, SP disassembles to produce IP, which it is suggested to boost protein degradation and cope with protein overload (42, 119, 129, 130). Since IP owns enhanced catalytic activity, it produces immunogenic polypeptides from both microbial- and oxidized/aggregated-proteins.…”

“…The IP is significantly up-regulated in glia and neurons, in both patients and experimental models of HD (121, 139), AD (112–117), PD (119, 120), MS (41, 98–103, 108–110), ALS (134, 140), neurotrauma (129), ischemic stroke (104, 124, 125), and epilepsy (38, 100, 126, 127). In the context of PD, the induction of IP within glia and DA neurons was recently related to alpha-synuclein degradation and subsequent generation of self-Ag peptides for T-cell presentation by MHC-I (79, 119, 132).…”

Microglial cell‐derived interleukin‐6 influences behavior and inflammatory response in the brain following traumatic brain injury

“…One example is Otopetrin 2 (Otop2), a proton‐selective channel required to cell signaling and pH regularization. A gene expression analysis of IFN‐γ‐activated microglia revealed upregulation of Otop2 expression (Moritz et al, ). Here, we observed that Otop2 expression would be upregulated by cryolesion and may be influenced by microglial Il6 deficiency, suggesting that microglia of lesioned mice would be activated, and microglia from Il6 ΔMic mice may be more activated than those of lesioned Il6 lox/lox mice (Figure b‐ii).…”

Molecular Insight Into the IRE1α-Mediated Type I Interferon Response Induced by Proteasome Impairment in Myeloid Cells of the Brain

“…Impairment of proteasomal function, reflected by intra-and extracellular protein aggregates, accompanied by disturbance of ER homeostasis as well as progressive tissue degeneration, is a hallmark of progressive neurodegenerative diseases (19)(20)(21)(22). In particular, several studies emphasize the role of microglia and, in particular, microglial proteasomes as potential mediators of the immune response that drives neurodegeneration or neuroinflammation (23)(24)(25)(26). In addition, consequences of altered proteasome dynamics on brain homeostasis and presumably microglia function became particularly evident in patients with proteasome-associated autoinflammatory syndromes (CANDLE/PRAAS), who harbor either homo-or heterozygous mutations in proteasome subunit genes.…”