The Unfolded Protein Response in Immune Cells as an Emerging Regulator of Neuroinflammation

Abstract

Immune surveillance is an essential process that safeguards the homeostasis of a healthy brain. Among the increasing diversity of immune cells present in the central nervous system (CNS), microglia have emerged as a prominent leukocyte subset with key roles in the support of brain function and in the control of neuroinflammation. In fact, impaired microglial function is associated with the development of neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD). Interestingly, these pathologies are also typified by protein aggregation and proteostasis dysfunction at the level of the endoplasmic reticulum (ER). These processes trigger activation of the unfolded protein response (UPR), which is a conserved signaling network that maintains the fidelity of the cellular proteome. Remarkably, beyond its role in protein folding, the UPR has also emerged as a key regulator of the development and function of immune cells. However, despite this evidence, the contribution of the UPR to immune cell homeostasis, immune surveillance, and neuro-inflammatory processes remains largely unexplored. In this review, we discuss the potential contribution of the UPR in brain-associated immune cells in the context of neurodegenerative diseases.

Pro-Inflammatory and Pro-Apoptotic Effects of the Non-Protein Amino Acid L-Azetidine-2-Carboxylic Acid in BV2 Microglial Cells

“…In fact, whereas protein misfolding in oligodendrocytes could potentially activate neighbouring microglia—causing cell activation—it cannot be excluded that AZE may directly trigger an inflammatory response after it enters the cell. This idea is supported by emerging evidence providing a link between ER stress-mediated activation of the UPR in microglia and cell polarization [ 14 ] and previous evidence of cell death and mitochondrial dysfunction in SH-SY5Y neuronal-like cells [ 39 ].…”

“…Recently, UPR has been studied in myeloid cells, where it was demonstrated to act as a fundamental proteostatic pathway to coordinate inflammatory responses [ 14 ]. Microglia, the resident innate immune cell of the CNS, are responsible for the ongoing CNS surveillance, the release of pro-inflammatory factors and act as scavengers to clear cellular and toxic debris [ 15 ].…”

Retinal Nerve Fiber Layer Thickness and Associations With Cognitive Impairment in Parkinson’s Disease

“…These humoral inflammatory or imaging biomarkers may provide valuable information for early identification, differential diagnosis, assessment of severity and even prognosis prediction for PD patients ( Avenali et al, 2020 ; Beheshti et al, 2020 ). As a window to the brain, the retina may consistently suffer inflammation and degeneration, and provide potential neuroimaging, or, neuroinflammatory markers ( Ramirez et al, 2017 ; Fernández et al, 2021 ). The uncovering of the disease-specific biomarker α-synuclein accompanied by the retinal progressive degeneration further emphasizes the potential role of the retina in the pathological process or pathogenesis of PD ( Adam et al, 2013 ; Bodis-Wollner, 2013 ; Bodis-Wollner et al, 2014 ; Ortuno-Lizaran et al, 2018 ).…”

CNS Redox Homeostasis and Dysfunction in Neurodegenerative Diseases

“…Besides aberrant inflammatory signaling described above, sustained ER stress compromises the protective function of the UPR in NDs, leading to the induction of apoptosis activating pathways and neuroinflammatory activation of glia. A growing body of evidence clearly indicates potential crosstalk between the UPR in immune cells and neuroinflammation [ 62 ].…”