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.

Nitric oxide (NO) is a versatile free radical that has been implicated in many biological processes (i.e., vasodilation, neurotransmission, and smooth muscle relaxation). High levels of NO, such as those produced by inducible NO synthase, are associated with innate immunity as well as tissue damage and disease pathology. Previous studies have characterized many stimuli that lead to NO production following central nervous system (CNS) infection, ischemia, and during neurodegeneration, but less is known about the effects of NO on the CNS resident astrocytes. Previously, excessive NO has been shown to impair protein folding leading to endoplasmic reticulum (ER) stress and initiation of the unfolded protein response. Previous studies have shown that ER stress drives activation of protein kinase R-like ER kinase (PERK) and Janus kinase-1 (JAK1) leading to inflammatory gene expression. We hypothesized that NO drives inflammatory processes within astrocytes through a similar process. To test this, we examined the effects of exogenous NO on primary cultures of murine astrocytes. Our data suggest that NO promotes a pro-inflammatory response that includes interleukin-6 and several chemokines. Our data show that NO induces phosphorylation of eukaryotic initiation factor 2 alpha; however, this and the inflammatory gene expression are independent of PERK. Knockdown of JAK1 using small interfering RNA reduced the expression of inflammatory mediators. Overall, we have identified that NO stimulates the integrated stress response and a JAK1-dependent inflammatory program in astrocytes. Summary statement: Murine astrocytes in culture respond to NO with increased expression of stress and inflammatory genes. The inflammatory stress response is independent of the ER stress-activated kinase PERK and is, in part, mediated by JAK1.

SARS-CoV-2 has caused an estimated 7 million deaths worldwide to date. A secreted SARS-CoV-2 accessory protein, known as open reading frame 8 (ORF8), elicits inflammatory pulmonary cytokine responses and is associated with disease severity in COVID-19 patients. Recent reports proposed that ORF8 mediates downstream signals in macrophages and monocytes through the IL-17 receptor complex (IL-17RA, IL-17RC). However, generally IL-17 signals are found to be restricted to the nonhematopoietic compartment, thought to be due to rate-limiting expression of IL-17RC. Accordingly, we revisited the capacity of IL-17 and ORF8 to induce cytokine gene expression in mouse and human macrophages and monocytes. In SARS-CoV-2–infected human and mouse lungs, IL17RC mRNA was undetectable in monocyte/macrophage populations. In cultured mouse and human monocytes and macrophages, ORF8 but not IL-17 led to elevated expression of target cytokines. ORF8-induced signaling was fully preserved in the presence of anti–IL-17RA/RC neutralizing Abs and in Il17ra−/− cells. ORF8 signaling was also operative in Il1r1−/− bone marrow–derived macrophages. However, the TLR/IL-1R family adaptor MyD88, which is dispensable for IL-17R signaling, was required for ORF8 activity yet MyD88 is not required for IL-17 signaling. Thus, we conclude that ORF8 transduces inflammatory signaling in monocytes and macrophages via MyD88 independently of the IL-17R.