Transcriptional Profiling Suggests Extensive Metabolic Rewiring of Human and Mouse Macrophages during Early Interferon Alpha Responses

Ahmed, Duale; Jaworski, Allison F.; Roy, David; Willmore, William G.; Golshani, Ashkan; Cassol, Edana

doi:10.1155/2018/5906819

Cited by 14 publications

(13 citation statements)

References 107 publications

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“…2, and Fig. 3;Ahmed et al, 2018;Boshuizen et al, 2016;Li et al, 2011a;Pulliam et al, 2014). Elevated scavenger receptors class A expression can also be found in human peripheral blood mononuclear cells (PBMCs) from subjects with elevated IFN signatures, such as SLE patients and HIV-infected individuals (Table 1 and Fig.…”

Section: Type-i Ifn-associated Cells In Atherogenesismentioning

confidence: 96%

“…Type-I IFNs have been shown to suppress both mouse and human macrophages' inflammatory cytokine production and inflammasome activity through antiinflammatory cytokine induction, such as IL-10, epigenetic regulation affecting chromatin accessibility, and metabolic rewiring, for instance, oxysterol 25-hydroxycholesterol production (Table 1 and Fig. 3; Ahmed et al, 2018;Cheng et al, 2019;Guarda et al, 2011;Reboldi et al, 2014). By contrast, upon type-I IFN stimulation, human peripheral monocyte-derived macrophages (MDMs) restore their inflammatory function silenced by TNF-induced LPS tolerance through reprogramming the accessibility of NF-κB-associated chromatin regions (Table 1; Park et al, 2017).…”

Section: Type-i Ifn-associated Cells In Atherogenesismentioning

confidence: 99%

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Type-I interferons in atherosclerosis

Chen

Tas

Winther

2019

Journal of Experimental Medicine

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The contribution of dyslipidemia and inflammation in atherosclerosis is well established. Along with effective lipid-lowering treatments, the recent success of clinical trials with anti-inflammatory therapies and the accelerated atherosclerosis in many autoimmune diseases suggest that targeting inflammation may open new avenues for the prevention and the treatment for cardiovascular diseases (CVDs). In the past decades, studies have widened the role of type-I interferons (IFNs) in disease, from antivirus defense to autoimmune responses and immuno-metabolic syndromes. While elevated type-I IFN level in serum is associated with CVD incidence in patients with interferonopathies, experimental data have attested that type-I IFNs affect plaque-residing macrophages, potentiate foam cell and extracellular trap formation, induce endothelial dysfunction, alter the phenotypes of dendritic cells and T and B lymphocytes, and lead to exacerbated atherosclerosis outcomes. In this review, we discuss the production and the effects of type-I IFNs in different atherosclerosis-associated cell types from molecular biology studies, animal models, and clinical observations, and the potential of new therapies against type-I IFN signaling for atherosclerosis.

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Section: Type-i Ifn-associated Cells In Atherogenesismentioning

confidence: 96%

Section: Type-i Ifn-associated Cells In Atherogenesismentioning

confidence: 99%

Type-I interferons in atherosclerosis

Chen

Tas

Winther

2019

Journal of Experimental Medicine

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“…The mouse studies were particularly informative because IFNα exposure was regulated. Although it has been demonstrated that type I IFN stimulation can increase OXPHOS and FAO in DCs and MCs 36 , 38 , inhibit isocitrate dehydrogenase (part of the TCA cycle) in macrophages 39 , and alter oxidative metabolism in other cells 61 , IFNα overexpression did not change metabolic signatures at early timepoints. However, there was an inverse relationship between the IGS and metabolic defects after LN onset, when the IGS recurred.…”

Section: Discussionmentioning

confidence: 92%

“…The IFN gene signature (IGS), a known hallmark of lupus 33 , 34 and lupus-affected tissues 35 , has been implicated in metabolic alteration of MCs 36 – 39 . To determine the functional relationship between IFN stimulation and metabolic alteration, we examined metabolic gene expression longitudinally in the IFNα-accelerated NZB/W murine model of LN, where the IGS increases at early timepoints following injection of IFNα adenovirus and then increases again when kidney disease develops (Fig.…”

Section: Resultsmentioning

confidence: 99%

Altered expression of genes controlling metabolism characterizes the tissue response to immune injury in lupus

Kingsmore

Bachali

Catalina

et al. 2021

Sci Rep

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To compare lupus pathogenesis in disparate tissues, we analyzed gene expression profiles of human discoid lupus erythematosus (DLE) and lupus nephritis (LN). We found common increases in myeloid cell-defining gene sets and decreases in genes controlling glucose and lipid metabolism in lupus-affected skin and kidney. Regression models in DLE indicated increased glycolysis was correlated with keratinocyte, endothelial, and inflammatory cell transcripts, and decreased tricarboxylic (TCA) cycle genes were correlated with the keratinocyte signature. In LN, regression models demonstrated decreased glycolysis and TCA cycle genes were correlated with increased endothelial or decreased kidney cell transcripts, respectively. Less severe glomerular LN exhibited similar alterations in metabolism and tissue cell transcripts before monocyte/myeloid cell infiltration in some patients. Additionally, changes to mitochondrial and peroxisomal transcripts were associated with specific cells rather than global signal changes. Examination of murine LN gene expression demonstrated metabolic changes were not driven by acute exposure to type I interferon and could be restored after immunosuppression. Finally, expression of HAVCR1, a tubule damage marker, was negatively correlated with the TCA cycle signature in LN models. These results indicate that altered metabolic dysfunction is a common, reversible change in lupus-affected tissues and appears to reflect damage downstream of immunologic processes.

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“…GO analysis identified the expected terms for interferon responses and, also interestingly, metabolic changes in catabolism. While caution should be borne in interpreting the directionality of biological pathways based solely on gene ontology terms, we note that IFNα and viral infection have been found to generally induce a catabolic state in various cell types including macrophages [66][67][68]. Deficiencies in microglial autophagy have also been recently linked to impaired synaptic pruning and autism-like behavioural defects [17].…”

Section: Discussionmentioning

confidence: 92%

Microglial responses to peripheral type 1 interferon

Zhang

Carroll

2020

J Neuroinflammation

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Background Interferon α (IFNα) is a cytokine whose production is increased endogenously in response to viral infection and in autoimmune diseases such as systemic lupus erythematosus (SLE). An elevated IFNα signature has been associated with clinically observed neuro-behavioural deficits such as mild cognitive impairment, fatigue, depression and psychosis in these diseases. However, the mechanisms underlying these neuropsychiatric symptoms remain largely unknown, and it is as yet unclear how IFNα signalling might influence central nervous system (CNS) function. Aberrant microglia-mediated synaptic pruning and function has recently been implicated in several neurodegenerative and neuropsychiatric diseases, but whether and how IFNα modulates these functions are not well defined. Methods Using a model of peripheral IFNα administration, we investigated gene expression changes due to IFNAR signalling in microglia. Bulk RNA sequencing on sorted microglia from wild type and microglia-specific Ifnar1 conditional knockout mice was performed to evaluate IFNα and IFNAR signalling-dependent changes in gene expression. Furthermore, the effects of IFNα on microglia morphology and synapse engulfment were assessed, via immunohistochemistry and flow cytometry. Results We found that IFNα exposure through the periphery induces a unique gene signature in microglia that includes the expected upregulation of multiple interferon-stimulated genes (ISGs), as well as the complement component C4b. We additionally characterized several IFNα-dependent changes in microglial phenotype, including expression of CD45 and CD68, cellular morphology and presynaptic engulfment, that reveal subtle brain region-specific differences. Finally, by specifically knocking down expression of IFNAR1 on microglia, we show that these changes are largely attributable to direct IFNAR signalling on microglia and not from indirect signalling effects through other CNS parenchymal cell types which are capable of IFNα-IFNAR signal transduction. Conclusions Peripheral IFNα induces unique genetic and phenotypic changes in microglia that are largely dependent on direct signalling through microglial IFNAR. The IFNα-induced upregulation of C4b could play important roles in the context of aberrant synaptic pruning in neuropsychiatric disease.

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Transcriptional Profiling Suggests Extensive Metabolic Rewiring of Human and Mouse Macrophages during Early Interferon Alpha Responses

Cited by 14 publications

References 107 publications

Type-I interferons in atherosclerosis

Type-I interferons in atherosclerosis

Altered expression of genes controlling metabolism characterizes the tissue response to immune injury in lupus

Microglial responses to peripheral type 1 interferon

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