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The Integrated Stress Response Promotes Macrophage Inflammation

ABSTRACT: Macrophages infiltrate islets early in the pathogenesis of Type 1 Diabetes (T1D), instigating islet inflammation and subsequent recognition by the adaptive immune system. A reanalysis of a publicly available single-cell RNA sequencing dataset from a pre-diabetic female non-obese diabetic (NOD) mouse revealed that the Integrated Stress Response (ISR), an evolutionarily conserved cellular pathway, is upregulated in macrophages during T1D progression. Triggered by environmental and pathological stressors, the ISR coordinates adaptive changes in gene expression to maintain cell functionality and survival and is identified as a candidate for targeted intervention. Following this, in vitro experiments on macrophage polarization and migration were conducted to evaluate changes resulting from ISR modulation. Results showed that ISR inhibition reduced the propensity of macrophages to polarize to a pro-inflammatory state without affecting anti-inflammatory polarization and reduced the migratory capabilities of pro-inflammatory macrophages. Observations from pre-diabetic female NOD mice administered ISRIB, a pharmacological ISR inhibitor, indicated a reduction in macrophage numbers within the islets, with increased PD-L1 expression on the macrophages.

ORGANISM(S): Mus musculus

PROVIDER: GSE278047 | GEO | 2024/10/28

REPOSITORIES: GEO

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Project description:This a model from the article: Modelling the onset of Type 1 diabetes: can impaired macrophage phagocytosis make the difference between health and disease? Maree AF, Kublik R, Finegood DT, Edelstein-Keshet L.Philos Transact A Math Phys Eng Sci.2006 May 15;364(1842):1267-82. 16608707, Abstract: A wave of apoptosis (programmed cell death) occurs normally in pancreatic beta-cells of newborn mice. We previously showed that macrophages from non-obese diabetic (NOD) mice become activated more slowly and engulf apoptotic cells at a lower rate than macrophages from control (Balb/c) mice. It has been hypothesized that this low clearance could result in secondary necrosis, escalating inflammation and self-antigen presentation that later triggers autoimmune, Type 1 diabetes (T1D). We here investigate whether this hypothesis could offer a reasonable and parsimonious explanation for onset of T1D in NOD mice. We quantify variants of the Copenhagen model (Freiesleben De Blasio et al. 1999 Diabetes 48, 1677), based on parameters from NOD and Balb/c experimental data. We show that the original Copenhagen model fails to explain observed phenomena within a reasonable range of parameter values, predicting an unrealistic all-or-none disease occurrence for both strains. However, if we take into account that, in general, activated macrophages produce harmful cytokines only when engulfing necrotic (but not apoptotic) cells, then the revised model becomes qualitatively and quantitatively reasonable. Further, we show that known differences between NOD and Balb/c mouse macrophage kinetics are large enough to account for the fact that an apoptotic wave can trigger escalating inflammatory response in NOD, but not Balb/c mice. In Balb/c mice, macrophages clear the apoptotic wave so efficiently, that chronic inflammation is prevented. This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team. For more information see the terms of use. To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

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The Integrated Stress Response Promotes Macrophage Inflammation

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