PERK-Dependent Activation of JAK1 and STAT3 Contributes to Endoplasmic Reticulum Stress-Induced Inflammation

Abstract

Neuroinflammation and endoplasmic reticulum (ER) stress are associated with many neurological diseases. Here, we have examined the interaction between ER stress and JAK/STAT-dependent inflammation in glial cells. We show that ER stress is present in the central nervous system (CNS) concomitant with inflammation and astrogliosis in the multiple sclerosis (MS) mouse model of experimental autoimmune encephalomyelitis (EAE). Astrocytes do not easily succumb to ER stress but rather activate an inflammatory program involving activation of STAT3 in a JAK1-dependent fashion. ER stress-induced activation of the JAK1/STAT3 axis leads to expression of interleukin 6 (IL-6) and several chemokines. Moreover, the activation of STAT3 signaling is dependent on PERK, a central component of the ER stress response, which we show is phosphorylated by JAK1. Disruption of PERK abrogates ER stress-induced activation of STAT3 and subsequent gene expression. Additionally, ER-stressed astrocytes, via paracrine signaling, can stimulate activation of microglia, leading to production of IL-6 and oncostatin M (OSM). These IL-6 cytokines can then synergize with ER stress in astrocytes to drive inflammation. Together, this work describes a new PERK/JAK1/STAT3 signaling pathway that elicits a feed-forward inflammatory loop involving astrocytes and microglia to drive neuroinflammation, which may be relevant in diseases such as MS.

Attenuation of PKR-like ER Kinase (PERK) Signaling Selectively Controls Endoplasmic Reticulum Stress-induced Inflammation Without Compromising Immunological Responses

“…Perturbations in the signaling molecules controlling the UPR can lead to functional changes in outcome. For example, we have shown previously (16) and show in Fig. 1 that astrocytes are highly resistant to ER stress.…”

“…ER Stress Augments Cytokine-induced Gene Expression in a PERK-dependent Fashion-Not only does ER stress stimulate inflammation, it can also alter the response to other inflammatory signals (16,23,24). To test whether PERK inhibition could modulate this effect, astrocytes were treated with the cytokines IL-1␤, OSM, or IFN-␥ individually or in the presence of thapsigargin.…”

“…Phenotype-We previously demonstrated that PERK-dependent communication between ER-stressed astrocytes and naïve microglia resulted in the activation of microglia (16). Therefore, we tested whether PERK inhibition could also modulate astrocyte-microglia interactions.…”

“…In addition to intracellular signaling in response to ER stress, there is also extracellular communication via cytokine and chemokine production (14). The ER stress pathway is coupled to inflammatory responses through activation of key signaling networks such as NF-B and JAK/STAT, leading to the production of cytokines, chemokines, and reactive species (15,16). In chronic diseases, ER stress and inflammation may collaborate to drive sustained inflammation (14).…”

FAD104, a Regulator of Adipogenesis and Osteogenesis, Interacts with the C-Terminal Region of STAT3 and Represses Malignant Transformation of Melanoma Cells

“…28) Additionally, protein kinase R-like ER kinase (PERK), an unfolded protein response (UPR) transducer localized to ER membrane, activates STAT3. 29) Moreover, it is reported that calreticulin, a chaperon protein involved in ER stress, promotes invasion and tumorigenesis through the activation of STAT3 signaling. 30) These findings provide evidence that there may be important interaction between ER-ER stress-STAT3 signaling and tumor progression.…”