Dietary Supplementation With Eicosapentaenoic Acid Inhibits Plasma Cell Differentiation and Attenuates Lupus Autoimmunity

Kobayashi, Azusa; Ito, Ayaka; Shirakawa, Ibuki; Tamura, Atsushi; Tomono, Susumu; Shindou, Hideo; Hedde, Per Niklas; Tanaka, Miyako; Tsuboi, Naotake; Ishimoto, Takuji; Akashi-Takamura, Sachiko; Maruyama, Shoichi; Suganami, Takayoshi

doi:10.3389/fimmu.2021.650856

Cited by 12 publications

(6 citation statements)

References 51 publications

(76 reference statements)

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“…Intriguingly, in both our in vivo and in vitro experiments, DHA suppresses the IFN1 pathway more strongly than other inflammatory pathways including NF-κB signaling. While Kobayashi and coworkers similarly found that the omega-3 fatty acids suppressed IFN1 gene expression in imiquimod (IMQ)-induced murine lupus ( 81 ), the underlying molecular mechanisms are unclear. Further investigations into how DHA preferentially suppresses could lead to novel therapies to effectively target this potent inflammatory response in autoimmune disease.…”

Section: Resultsmentioning

confidence: 99%

Single cell analysis of docosahexaenoic acid suppression of sequential LPS-induced proinflammatory and interferon-regulated gene expression in the macrophage

et al. 2022

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Preclinical and clinical studies suggest that consumption of long chain omega-3 polyunsaturated fatty acids (PUFAs) reduces severity of chronic inflammatory and autoimmune diseases. While these ameliorative effects are conventionally associated with downregulated expression of proinflammatory cytokine and chemokine genes, our laboratory has recently identified Type 1 interferon (IFN1)-regulated gene expression to be another key target of omega-3 PUFAs. Here we used single cell RNA sequencing (scRNAseq) to gain new mechanistic perspectives on how the omega-3 PUFA docosahexaenoic acid (DHA) influences TLR4-driven proinflammatory and IFN1-regulated gene expression in a novel self-renewing murine fetal liver-derived macrophage (FLM) model. FLMs were cultured with 25 µM DHA or vehicle for 24 h, treated with modest concentration of LPS (20 ng/ml) for 1 and 4 h, and then subjected to scRNAseq using the 10X Chromium System. At 0 h (i.e., in the absence of LPS), DHA increased expression of genes associated with the NRF2 antioxidant response (e.g. Sqstm1, Hmox1, Chchd10) and metal homeostasis (e.g.Mt1, Mt2, Ftl1, Fth1), both of which are consistent with DHA-induced polarization of FLMs to a more anti-inflammatory phenotype. At 1 h post-LPS treatment, DHA inhibited LPS-induced cholesterol synthesis genes (e.g. Scd1, Scd2, Pmvk, Cyp51, Hmgcs1, and Fdps) which potentially could contribute to interference with TLR4-mediated inflammatory signaling. At 4 h post-LPS treatment, LPS-treated FLMs reflected a more robust inflammatory response including upregulation of proinflammatory cytokine (e.g. Il1a, Il1b, Tnf) and chemokine (e.g.Ccl2, Ccl3, Ccl4, Ccl7) genes as well as IFN1-regulated genes (e.g. Irf7, Mx1, Oasl1, Ifit1), many of which were suppressed by DHA. Using single-cell regulatory network inference and clustering (SCENIC) to identify gene expression networks, we found DHA modestly downregulated LPS-induced expression of NF-κB-target genes. Importantly, LPS induced a subset of FLMs simultaneously expressing NF-κB- and IRF7/STAT1/STAT2-target genes that were conspicuously absent in DHA-pretreated FLMs. Thus, DHA potently targeted both the NF-κB and the IFN1 responses. Altogether, scRNAseq generated a valuable dataset that provides new insights into multiple overlapping mechanisms by which DHA may transcriptionally or post-transcriptionally regulate LPS-induced proinflammatory and IFN1-driven responses in macrophages.

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Section: Resultsmentioning

confidence: 99%

Single cell analysis of docosahexaenoic acid suppression of sequential LPS-induced proinflammatory and interferon-regulated gene expression in the macrophage

et al. 2022

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“…Alterations in the activation of immunocytes caused by omega-3 fatty acids (a family of polyunsaturated fatty acids, PUFAs) have been described for many years (136). Supplementation with omega-3 FAs could reduce autoantibody production and immunocomplex deposition, and hinder interferon and chemokine gene expression in lupus (137,138). Consistently, dietary short-chain FAs can regulate B cell differentiation, which critically underpins effective T-dependent and T-independent antibody responses in lupus-prone mice (139).…”

Section: Lipid Metabolism In Lymphocytes In Slementioning

confidence: 99%

Lipid Metabolism: Immune Regulation and Therapeutic Prospectives in Systemic Lupus Erythematosus

Sun

Cai

et al. 2022

Front. Immunol.

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Systemic lupus erythematosus (SLE) is a heterogeneous disease characterized by the production of abnormal autoantibodies and immune complexes that can affect the organ and organ systems, particularly the kidneys and the cardiovascular system. Emerging evidence suggests that dysregulated lipid metabolism, especially in key effector cells, such as T cells, B cells, and innate immune cells, exerts complex effects on the pathogenesis and progression of SLE. Beyond their important roles as membrane components and energy storage, different lipids can also modulate different cellular processes, such as proliferation, differentiation, and survival. In this review, we summarize altered lipid metabolism and the associated mechanisms involved in the pathogenesis and progression of SLE. Furthermore, we discuss the recent progress in the role of lipid metabolism as a potential therapeutic target in SLE.

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“…Higher dietary sodium and lower dietary potassium intake were significantly correlated with C-reactive protein (CRP), which may lead to an increase in disease severity [ 124 ]. A diet rich in eicosapentaenoic acid (EPA) was found to ameliorate the lupus nephritis manifestations including immune complex accumulation and autoantibody generation in the kidney [ 125 ].…”

Section: Environmental Factorsmentioning

confidence: 99%

Systemic lupus erythematosus: latest insight into etiopathogenesis

et al. 2023

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Systemic lupus erythematosus (SLE) is a complex autoimmune disorder of unknown etiology. Multifactorial interaction among various susceptible factors such as environmental, hormonal, and genetic factors makes it more heterogeneous and complex. Genetic and epigenetic modifications have been realized to regulate the immunobiology of lupus through environmental modifications such as diet and nutrition. Although these interactions may vary from population to population, the understanding of these risk factors can enhance the perception of the mechanistic basis of lupus etiology. To recognize the recent advances in lupus, an electronic search was conducted among search engines such as Google Scholar and PubMed, where we found about 30.4% publications of total studies related to genetics and epigenetics, 33.5% publications related to immunobiology and 34% related to environmental factors. These outcomes suggested that management of diet and lifestyle have a direct relationship with the severity of lupus that influence via modulating the complex interaction among genetics and immunobiology. The present review emphasizes the knowledge about the multifactorial interactions between various susceptible factors based on recent advances that will further update the understanding of mechanisms involved in disease pathoetiology. Knowledge of these mechanisms will further assist in the creation of novel diagnostic and therapeutic options.

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Dietary Supplementation With Eicosapentaenoic Acid Inhibits Plasma Cell Differentiation and Attenuates Lupus Autoimmunity

Cited by 12 publications

References 51 publications

Single cell analysis of docosahexaenoic acid suppression of sequential LPS-induced proinflammatory and interferon-regulated gene expression in the macrophage

Single cell analysis of docosahexaenoic acid suppression of sequential LPS-induced proinflammatory and interferon-regulated gene expression in the macrophage

Lipid Metabolism: Immune Regulation and Therapeutic Prospectives in Systemic Lupus Erythematosus

Systemic lupus erythematosus: latest insight into etiopathogenesis

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