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. Author manuscript; available in PMC: 2021 Jul 16.
Published in final edited form as: Trends Immunol. 2020 Aug 13;41(9):805–819. doi: 10.1016/j.it.2020.07.007

Figure 3. Control of Mouse and Human Astrocytes by the Unfolded Protein Response (UPR) and Environmental Chemicals.

Figure 3.

Platform for the unbiased identification of environmental factors that affect astrocyte responses. A small-molecule screen on a collection of environmental chemicals provided by the US Environmental Protection Agency (EPA) identified the herbicide linuron as an environmental chemical that increases inducible nitric oxide synthase (iNOS) expression in astrocyte-like cells in a novel zebrafish model of neurodegeneration; these findings were later validated in mouse and human astrocyte models. Computational modeling, genetic, and small-molecule perturbation studies on murine and human systems identified the mechanism of action of linuron, which activates the UPR via sigma non-opioid intracellular receptor 1 (SIGMAR1)–inositol-requiring enzyme 1 α (IRE1α)–X-box binding protein 1 (XBP1) signaling. UPR signaling is also activated and drives astrocyte proinflammatory programs even in the absence of linuron during experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS) [93]. Csf2, colony-stimulating factor 2; ER, endoplasmic reticulum; Edem1, ER degradation-enhancing alpha-mannosidase-like protein 1; Nos2, nitric oxide synthase 2; XBP1s, X-box binding protein 1 spliced form; XBP1u, X-box binding protein 1 unspliced form. This figure was created using BioRender (https://biorender.com/).