Amelioration of Murine Macrophage Activation Syndrome by Monomethyl Fumarate in Both a Heme Oxygenase 1–Dependent and Heme Oxygenase 1–Independent Manner

Biswas, Chhanda; Chu, Niansheng; Burn, Thomas N.; Kreiger, Portia A.; Behrens, Edward M.

doi:10.1002/art.41591

Cited by 5 publications

(6 citation statements)

References 41 publications

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“…Slides were read with grading of lobular inflammatory score, necrosis, steatosis, portal inflammation and endothelial injury score by pediatric pathologist blinded to treatment protocols (PAK). The established grading criteria of endothelial injury were previously published [ 21 ]. Images were acquired on an Eclipse 90i microscope (Nikon, Melville, NY) using NIE-ELEMENTS software.…”

Section: Methodsmentioning

confidence: 99%

Familial hemophagocytic lymphohistiocytosis hepatitis is mediated by IFN-γ in a predominantly hepatic-intrinsic manner

et al. 2022

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Interferon gamma (IFN-γ) is the main cytokine driving organ dysfunction in Familial Hemophagocytic Lymphohistiocytosis (FHL). Blockade of IFN-γ pathway ameliorates FHL hepatitis, both in animal models and in humans with FHL. Hepatocytes are known to express IFN-γ receptor (IFN-γ-R). However, whether IFN-γ induced hepatitis in FHL is a lymphocyte or liver intrinsic response to the cytokine has yet to be elucidated. Using a IFNgR−/− bone marrow chimeric model, this study showed that non-hematopoietic IFN-γ response is critical for development of FHL hepatitis in LCMV-infected Prf1−/− mice. Lack of hepatic IFN-γ responsiveness results in reduced hepatitis as measured by hepatomegaly, alanine aminotransferase (ALT) levels and abrogated histologic endothelial inflammation. In addition, IFN-γ non-hematopoietic response was critical in activation of lymphocytes by soluble interleukin 2 receptor (sIL-2r) and recruitment of CD8+ effector T lymphocytes (CD8+ CD44hi CD62Llo) (Teff) and inflammatory monocytes. Lastly, non-hematopoietic IFN-γ response results in increased hepatic transcription of type 1 immune response and oxidative stress response pathways, while decreasing transcription of genes involved in extracellular matrix (ECM) production. In summary, these findings demonstrate that there is a hepatic transcriptional response to IFN-γ, likely critical in the pathogenesis of FHL hepatitis and hepatic specific responses could be a therapeutic target in this disorder.

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Section: Methodsmentioning

confidence: 99%

Familial hemophagocytic lymphohistiocytosis hepatitis is mediated by IFN-γ in a predominantly hepatic-intrinsic manner

et al. 2022

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“…Further studies confirmed that MAS manifestations in this model require both CpG and IFN-γ signaling [ 57 ]. Related to IL-10, a recent report suggested heme oxygenase 1 (HO-1) regulates production of IL-10 and that monomethyl fumarate, a drug activating HO-1 production, ameliorates MAS features [ 58 ].…”

Section: Animal Models For Mas and Sjiamentioning

confidence: 99%

Mouse models of systemic juvenile idiopathic arthritis and macrophage activation syndrome

Inoue

Schulert

2023

Arthritis Res Ther

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Macrophage activation syndrome (MAS) is a life-threatening complication of pediatric rheumatic diseases, occurring most commonly in children with systemic juvenile idiopathic arthritis (SJIA). Despite several classes of currently available treatment options for SJIA, including biologic agents targeting IL-1 or IL-6, there remain severe cases suffering from refractory disease and recurrent MAS. The phenotype of MAS is similar to hemophagocytic lymphohistiocytosis (HLH), but the underlying pathophysiology of MAS complicating SJIA or other disorders has not been fully clarified. These facts make it challenging to develop and utilize animal models to study MAS. To date, there is no “perfect” model replicating MAS, but several models do demonstrate aspects of SJIA and/or MAS. In this review, we examine the proposed animal models of SJIA and MAS, focusing on how they reflect these disorders, what we have learned from the models, and potential future research questions. As we better understand the key features of each, animal models can be powerful tools to further define the pathophysiology of SJIA and MAS, and develop new treatment targets and strategies.

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“…We have previously demonstrated that the small molecule monomethyl fumarate (MMF) is able to ameliorate CpG-induced murine hyperinflammation in a HO1-dependent and HO1-independent manner [4]. Publications from our lab and others have revealed MMF as a potent inducer of transcription factor NRF2, which is well established as a critical sensor and regulator of antioxidant cellular pathways.…”

Section: Resultsmentioning

confidence: 99%

“…Secondary hyperinflammatory disease was induced by repeat activation of TLR-9 as previously described [4]. Briefly, 7 to 10-week-old mice were injected with 5 doses of phosphate buffered saline (PBS) or 50 μg of CpG 1826 intraperitoneally every other day for 9 days.…”

Section: Cpg-induced Hyperinflammationmentioning

confidence: 99%

“…Findings from our lab has demonstrated that HO1 is not only an interesting biomarker for hyperinflammatory processes, but also an important mediator of disease. For example, we have found that the small molecule monomethyl fumarate (MMF) is able to ameliorate CpG-induced murine hyperinflammation in a HO1-dependent and HO1-independent manner [4]. MMF and its relative dimethyl fumarate are potent inducers of transcription factor NRF2, which is well established as a critical sensor and regulator of antioxidant cellular pathways [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

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Transcription Factor NRF2 is Activated by Erythrophagocytosis of Oxidized Red Blood Cell Products and Suppresses the IL-12-IFNg-IL-10 Axis in a Murine Model of Hyperinflammatory Disease

Gallo,

Elliott,

Ford

et al. 2023

Preprint

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Hyperinflammatory diseases including macrophage activation syndrome (MAS) and hemophagocytic lymphohistocytosis (HLH) are characterized by multi-lineage cytopenias, hypercytokinemia, and tissue hemophagocytosis. However, the mechanisms by which erythrophagocytosis mediates iron metabolism and regulates the hyperactive immune response remain unclear. The transcription factor NRF2 is an important sensor for inflammatory and redox distress. The targets of NRF2 are antioxidant response elements responsible for transcription of genes related to restoration of redox homeostasis within the cell. Here we demonstrate that mice with CpG-induced MAS have evidence of systemic oxidative and nitrosative distress – including increased serum nitric oxide and elevated systemic lipid peroxidation. In this model, NRF2 knockout mice develop significantly worse organomegaly, hypercytokinemia, and reticulocytosis. NRF2 knockout mice have unexpected exacerbation in the cytokines that are central to hyperinflammatory physiology – namely IL-12, IFN gamma (IFNg), and IL-10.In vitrowe demonstrate that oxidized red blood cell products and heme itself suppress IL-12 protein production and transcription from bone marrow derived dendritic cells in a NRF2-dependent manner. Together our studies demonstrate that erythrophagocytosis of oxidized red blood cell products suppresses the Il-12-IFNg-IL-10 axis which drives hyperinflammation in murine hyperinflammation.Graphical abstractCreated with BioRender

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Amelioration of Murine Macrophage Activation Syndrome by Monomethyl Fumarate in Both a Heme Oxygenase 1–Dependent and Heme Oxygenase 1–Independent Manner

Cited by 5 publications

References 41 publications

Familial hemophagocytic lymphohistiocytosis hepatitis is mediated by IFN-γ in a predominantly hepatic-intrinsic manner

Familial hemophagocytic lymphohistiocytosis hepatitis is mediated by IFN-γ in a predominantly hepatic-intrinsic manner

Mouse models of systemic juvenile idiopathic arthritis and macrophage activation syndrome

Transcription Factor NRF2 is Activated by Erythrophagocytosis of Oxidized Red Blood Cell Products and Suppresses the IL-12-IFNg-IL-10 Axis in a Murine Model of Hyperinflammatory Disease

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