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GNPS - Metabolic and Proteomic Changes in Sickle Cell Disease and thalassemia Mouse Splenic and Hepatic Macrophages and Peripheral Blood Mononuclear cells

ABSTRACT: Sickle cell disease and Beta-thalassemia represent hemoglobinopathies arising from dysfunctional or under produced beta-globin chains, respectively. In both diseases, red blood cell injury and anemia are the impetus for end organ injury. Because persistent erythrophagocytosis is a hallmark of these genetic maladies it is critical to understand how macrophage phenotype polarizations in tissue compartments can inform on disease progression. Murine models of sickle cell disease and Beta-thalassemia allow for a basic understanding of mechanisms and provide for translation to human disease. A multi-omics approach to understanding macrophage metabolism and protein changes in two murine models of beta-globinopathy was performed on peripheral blood mononuclear cells as well as spleen and liver macrophages isolated from Berkley sickle cell disease (Berk-ss) and heterozygous B1/B2 globin gene deletion (Hbbth3/+) mice. Results from these experiments revealed the metabolome and proteome of macrophages are polarized to a distinct phenotype in Berk-ss and Hbbth3/+ compared each other and their common background mice (C57BL6/J). Further, spleen and liver macrophages revealed distinct disease specific phenotypes, suggesting macrophages become differentially polarized and reprogrammed within tissue compartments. We conclude that tissue recruitment, polarization, metabolic and proteomic reprogramming of macrophages in Berk-ss and Hbb mice may be relevant to disease to progression in other tissue.

INSTRUMENT(S): timsTOF Pro 2

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Angelo D'alessandro David Irwin

PROVIDER: MSV000092457 | GNPS | Mon Jul 17 08:36:00 BST 2023

REPOSITORIES: GNPS

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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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GNPS - Metabolic and Proteomic Changes in Sickle Cell Disease and thalassemia Mouse Splenic and Hepatic Macrophages and Peripheral Blood Mononuclear cells

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