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Nitric Oxide Induces a Janus Kinase-1-Dependent Inflammatory Response in Primary Murine Astrocytes.

ABSTRACT: 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.

SUBMITTER: Nowery JD

PROVIDER: S-EPMC8588800 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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-? (TNF-?) 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) 45? 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 GADD45? 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.

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Nitric Oxide Induces a Janus Kinase-1-Dependent Inflammatory Response in Primary Murine Astrocytes.

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