The role of endoplasmic reticulum stress in astrocytes.

Astrocytes are glial cells that support neurological function in the central nervous system (CNS), in part, by providing structural support for neuronal synapses and blood vessels, participating in electrical and chemical transmission, and providing trophic support via soluble factors. Dysregulation of astrocyte function contributes to neurological decline in CNS diseases. Neurological diseases are highly heterogeneous but share common features of cellular stress including the accumulation of misfolded proteins. Endoplasmic reticulum (ER) stress has been reported in nearly all neurological and neurodegenerative diseases. ER stress occurs when there is an accumulation of misfolded proteins in the ER lumen and the protein folding demand of the ER is overwhelmed. ER stress initiates the unfolded protein response (UPR) to restore homeostasis by abating protein translation and, if the cell is irreparably damaged, initiating apoptosis. Although protein aggregation and misfolding in neurological disease has been well described, cell-specific contributions of ER stress and the UPR in physiological and disease states are poorly understood. Recent work has revealed a role for active UPR signaling that may drive astrocytes toward a maladaptive phenotype in various model systems. In response to ER stress, astrocytes produce inflammatory mediators, have reduced trophic support, and can transmit ER stress to other cells. This review will discuss the current known contributions and consequences of activated UPR signaling in astrocytes.

Janus Kinase 1 Is Required for Transcriptional Reprograming of Murine Astrocytes in Response to Endoplasmic Reticulum Stress.

Neurodegenerative diseases are associated with the accumulation of misfolded proteins in the endoplasmic reticulum (ER), leading to ER stress. To adapt, cells initiate the unfolded protein response (UPR). However, severe or unresolved UPR activation leads to cell death and inflammation. The UPR is initiated, in part, by the trans-ER membrane kinase PKR-like ER kinase (PERK). Recent evidence indicates ER stress and inflammation are linked, and we have shown that this involves PERK-dependent signaling via Janus Kinase (JAK) 1. This signaling provokes the production of soluble inflammatory mediators such as interleukin-6 (IL-6) and chemokine C-C motif ligand 2 (CCL2). We, therefore, hypothesized that JAK1 may control widespread transcriptional changes in response to ER stress. Here, using RNA sequencing of primary murine astrocytes, we demonstrate that JAK1 regulates approximately 10% of ER stress-induced gene expression and is required for a subset of PERK-dependent genes. Additionally, ER stress synergizes with tumor necrosis factor-α (TNF-α) to drive inflammatory gene expression in a JAK1-dependent fashion. We identified that JAK1 contributes to activating transcription factor (ATF) 4-dependent gene expression, including expression of the genes growth arrest and DNA damage (GADD) 45α and tribbles (TRIB) 3 that have not previously been associated with JAK signaling. While these genes are JAK1 dependent in response to ER stress, expression of GADD45α and TRIB3 are not induced by the JAK1-activating cytokine, oncostatin M (OSM). Transcriptomic analysis revealed that JAK1 drives distinct transcriptional programs in response to OSM stimulation versus ER stress. Interestingly, JAK1-dependent genes induced by ER stress in an ATF4-dependent mechanism were unaffected by small molecule inhibition of JAK1, suggesting that, in response to UPR activation, JAK1 initiates gene expression using non-canonical mechanisms. Overall, we have identified that JAK1 is a major regulator of ER stress-induced gene expression.

Endoplasmic reticulum stress differentially modulates the IL-6 family of cytokines in murine astrocytes and macrophages.

In many diseases, misfolded proteins accumulate within the endoplasmic reticulum (ER), leading to ER stress. In response, the cell initiates the unfolded protein response (UPR) to reestablish homeostasis. Additionally, in response to ER stress, various cell types mount an inflammatory response involving interleukin (IL)-6. While IL-6 has been widely studied, the impact of ER stress on other members of the IL-6 cytokine family, including oncostatin (OSM), IL-11, ciliary neurotrophic factor (CNTF), and leukemia inhibitor factor (LIF) remains to be elucidated. Here, we have examined the expression of the IL-6 family cytokines in response to pharmacologically-induced ER stress in astrocytes and macrophages, which express IL-6 in response to ER stress through different mechanisms. Our findings indicate that, in astrocytes, ER stress regulates mRNA expression of the IL-6 family of cytokines that is, in part, mediated by PKR-like ER kinase (PERK) and Janus kinase (JAK) 1. Additionally, in astrocytes, CNTF expression was suppressed through a PERK-dependent mechanism. Macrophages display a different profile of expression of the IL-6 family that is largely independent of PERK. However, IL-6 expression in macrophages was dependent on JAK signaling. Overall, this study demonstrates the cell-specific and differential mechanisms controlling expression of the IL-6 family of cytokines in response to ER stress.

Endoplasmic reticulum stress and inflammation in the central nervous system.

Persistent endoplasmic reticulum (ER) stress is thought to drive the pathology of many chronic disorders due to its potential to elicit aberrant inflammatory signaling and facilitate cell death. In neurodegenerative diseases, the accumulation of misfolded proteins and concomitant induction of ER stress in neurons contributes to neuronal dysfunction. In addition, ER stress responses induced in the surrounding neuroglia may promote disease progression by coordinating damaging inflammatory responses, which help fuel a neurotoxic milieu. Nevertheless, there still remains a gap in knowledge regarding the cell-specific mechanisms by which ER stress mediates neuroinflammation. In this review, we will discuss recently uncovered inflammatory pathways linked to the ER stress response. Moreover, we will summarize the present literature delineating how ER stress is generated in Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis, and Multiple Sclerosis, and highlight how ER stress and neuroinflammation intersect mechanistically within the central nervous system. The mechanisms by which stress-induced inflammation contributes to the pathogenesis and progression of neurodegenerative diseases remain poorly understood. Further examination of this interplay could present unappreciated insights into the development of neurodegenerative diseases, and reveal new therapeutic targets.

A patterned porous polymer film for localized capture of insulin and glucose-responsive release.

A glucose-responsive, porous polymer film which can be used for controlled insulin release was fabricated. By mixing a polystyrene-dichloromethane solution containing didodecylamine with water, with thorough shaking, a reverse microemulsion was achieved. After spreading the microemulsion on a glass slide and evaporating the solvent, an ordered honeycomb-patterned film was produced, accompanied by an accumulation of didodecylamine within the inner surface of the cavities. The patterned cavities were further modified with poly(acrylic acid), 3-aminophenylboronic acid, and alginate so that they would entrap insulin aggregates. The insulin aggregates were prepared using a salting-out method and were incorporated into the cavities by an electrostatic interaction with the alginate. Under the stimulus of glucose, insulin aggregates were released from the cavities and further calculations demonstrated that there was a very high efficiency of release. In contrast, in an aqueous solution without glucose, almost no insulin was released from the cavities. This investigation demonstrates that it is feasible for porous polymer films, whose cavities act as a protein reservoir, to be used as a glucose-responsive insulin delivery vehicle, which may have potential as a controlled-release drug-delivery system for the treatment of diabetes.