Inhibition of the Immunoproteasome Subunit LMP7 Ameliorates Cerebral White Matter Demyelination Possibly via TGFβ/Smad Signaling

Abstract

Objectives. Chronic cerebral hypoperfusion induces white matter ischemic injury and cognitive impairment, whereas the mechanism remains unclear. Immunoproteasomes have been implicated in the pathogenesis of acute ischemia stroke and multiple sclerosis. However, the expression and role of immunoproteasomes in the brain of chronic cerebral hypoperfusion remain to be clarified. Methods. Chronic white matter ischemic injury mice models were induced by bilateral carotid artery stenosis (BCAS). A selective immunoproteasome subunit low-molecular-mass peptide-7 (LMP7) inhibitor PR957 was administered to mice. Cognitive function, white matter integrity, and potential pathways were assessed after BCAS. Results. The present study found that chronic cerebral hypoperfusion following BCAS induced cerebral white matter demyelination and cognitive impairment, accompanied with elevated expression of the immunoproteasomes LMP2 and LMP7, activation of astrocytes and microglia, and increased production of inflammatory cytokines (e.g., interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), IL-10, transforming growth factor-β1 (TGFβ1), and insulin-like growth factor-1 (IGF-1)). However, inhibition of LMP7 with the specific proteasome inhibitor PR957 significantly mitigated the histological damage of the white matter, suppressed inflammatory response, and paralleled by an improvement of cognitive function. Furthermore, treatment of PR957 significantly upregulated the level of TGFβ1, the total expression level, and the phosphorylation level of Smad2/3 and promoted brain remyelination. Surprisingly, PR957 alone had no effects on the neuroinflammation response and the activation of TGFβ/Smad signaling in the sham-operated (BCAS-nonoperated) mice. Conclusions. The possible mechanism underlying this was attributed to that the immunoproteasome regulates TGFβ/Smad signaling-mediated neuroinflammation and oligodendrocyte remyelination.

Exploring the hub mechanisms of ischemic stroke based on protein-protein interaction networks related to ischemic stroke and inflammatory bowel disease

“…Down-regulation of three subunits of the proteasome (PSMA2, PSMA3, and PSMA4) genes to regulate cellular functions against oxidative stress, which has the effect of reducing atherosclerosis 59 . Specific proteasome inhibitor PR957 inhibited LMP7 and significantly attenuated histological damage to the cerebral white matter and the cognitive function in ischemic stroke by suppressing the inflammatory response 60 .…”

Downregulation of SIRT1, SIRT3, and IGF-1 in ApoE-deficient mice exacerbates neuronal damage induced by chronic cerebral hypoperfusion

“…In rats with right carotid artery ligation and hypoxic exposure, administration of exogenous IGF-1 reduced the manifestations of periventricular leukomalacia, increased the number of surviving mature neurons in the cerebral cortex (Kim et al, 2021). When reproducing bilateral carotid artery stenosis in mice, white matter injury, an increase in IGF-1 expression, and the involvement of the LMP7 immunoproteasome in the regulation of TGFβ/Smad-mediated neuroinflammation, oligodendrocyte remyelination and cognitive impairment were demonstrated (Chen et al, 2021). Antagonists or IGF-1R silencing reversed neuroprotection against white matter damage, apoptosis, and oligodendrocyte demyelination in chronic cerebral hypoperfusion in mice and its induced vascular dementia (Youssef et al, 2020), demonstrating a protective role of IGF-1-mediated signaling pathways in damage to white matter and the development of cognitive deficits.…”

“…IGF-1 has been shown to be involved in neuroprotection in brain ischemic stroke, cerebral trauma, Alzheimer's disease, amyotrophic lateral sclerosis, epilepsy, neurological dysfunctions, and, in vessels, can prevent atherosclerotic lesions (Bianchi et al, 2017;Lu et al, 2020;Bhalla et al, 2022;Ge et al, 2022;Wang et al, 2022;Sukhanov et al, 2023). However, the role of IGF-1 and its receptors in chronic cerebral hypoperfusion has been investigated only in a few works (Youssef et al, 2020;Chen et al, 2021;Kim et al, 2021) and needs clarification.…”

LMP2 deficiency causes abnormal metabolism, oxidative stress, neuroinflammation, myelin loss and neurobehavioral dysfunctions

“…Coronal Sects. (20 μm) were stained with Luxol Fast Blue Stain Kit according to the manufacturer’s instructions (Abcam, USA) and conducted as described previously [ 20 ]. The severity of the white matter lesions was graded as described [ 21 ].…”