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.

Keywords: ER stress; UPR; immune system; inflammation; microglia; neurodegeneration; neuroinflammation; protein misfolding.

Figure 1

The unfolded protein response (UPR). Endoplasmic reticulum (ER) stress induces an adaptive response known as the unfolded protein response (UPR), which is controlled by three main ER-resident sensors: IRE1, PERK, and activating transcription factor-6 (ATF6). (A) IRE1 is activated by oligomerization and trans-phosphorylation upon binding of unfolded proteins and release of the chaperone BiP. IRE1 autophosphorylation leads to the activation of its RNase domain and the processing of the mRNA encoding for X-box binding protein 1 (XBP1s), a transcriptional factor that upregulates genes involved in protein folding and quality control, in addition to regulating ER/Golgi biogenesis and ER-mediated degradation (ERAD), lipid biogenesis and cytokine production. Additionally, IRE1 RNase also degrades a subset of specific RNAs and microRNAs, a process termed Regulated IRE1-Dependent Decay (RIDD). (B) Upon activation, PERK phosphorylates the eukaryotic initiation factor-2α (eIF2α), decreasing the synthesis of proteins and the overload of misfolded proteins at the ER. PERK phosphorylation also leads to the specific translation of ATF4, a transcription factor that promotes the expression of genes related to amino acid metabolism, antioxidant response, autophagy, and apoptosis. (C) ATF6 is activated upon release of BiP and is translocated to the Golgi, where it undergoes sequential cleavage and removal of its luminal domain. The remaining transactivation domain of ATF6 moves to the nucleus and coordinates the expression of genes encoding ER chaperones, ER-associated protein degradation (ERAD) components, and molecules involved in lipid biogenesis. Figure created with BioRender.com.

Figure 2

Potential roles of the UPR in immune cells during neurodegeneration. Protein aggregates and myelin debris can promote inflammation via triggering of innate receptors and activation of the UPR, which in turn could increase inflammation in neurodegenerative diseases mainly by enhancing the production of proinflammatory cytokines and chemokines. (a) Detection of proteins aggregates (Amyloid-β, α-synuclein, neurofibrillary tangles) and myelin debris through TLR2 and TLR4 (and probably others pattern recognition receptors) present on immune cells can activate the IRE1/XBP1s axis through reactive oxygen species (ROS) production by NOX2. (b) PERK can modulate the production of the pro-inflammatory cytokines IL-6, TNF, IL-1β, and the chemokines CCL2 and CCL20 through activation of JAK1-STAT3 and JAK2-STAT1 signaling pathways. (c) PERK also can control the synthesis of IL-23 via CHOP. (d) Additionally, PERK could control the synthesis of type I interferons. (e) ATF6 via NF-κB can enhance the production of the cytokines IL-6, TNF, and the chemokines CCL2 and CCL8. (f) The kinase domain of IRE1 can modulate the production of IL-6, TNF, and IL-1β through activation of NF-κB via JNK and NOD1/2 receptors. (g) BP1s can promote optimal production of IL-6, TNF, and type I IFNs and also favors the synthesis of IL-23. (h) IRE1 RNase via RIDD activates the NLRP3 inflammasome through degradation of the TXNIP-destabilizing microRNA miR-17, leading to IL-1β production. (i) Sigmar1 forms a complex with binding immunoglobulin protein (BiP) under normal conditions, but Sigmar1 agonists can dissociate Sigmar1 from Bip to induce its action as a chaperone protein. Sigmar1 interacts with IRE1 and stabilizes it, prolonging IRE1/XBP1s signaling. Figure created with BioRender.com.