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Rsad2 is necessary for mouse dendritic cell maturation via the IRF7-mediated signaling pathway.

ABSTRACT: Dendritic cells (DCs) are the most potent professional antigen presenting cells and inducers of T cell-mediated immunity. However, few specific markers of mature DCs (mDC) have been reported. A previous microarray analysis revealed expression of mDC-specific genes and identified Rsad2 (radical S-adenosyl methionine domain containing 2) as a candidate specific marker for DC maturation. Mouse bone marrow-derived DCs were transfected with Rsad2 siRNA and examined by flow cytometry, ELISA, western, and confocal microscopy. C57BL/6 mice received intravenously B16F10 cells to establish a pulmonary metastasis model. Tumor-bearing mice then received subcutaneously two injections of mDCs or Rsad2 knockdown DCs. The cytotoxic T lymphocyte (CTL) population was examined from splenocytes of DC-vaccinated mice by flow cytometry. Rsad2 was induced at high levels in LPS-stimulated mDCs and mDC function was markedly attenuated under conditions of Rsad2 knockdown. Moreover, Rsad2 was necessary for mDC maturation via the IRF7-mediated signaling pathway. The importance of Rsad2 was confirmed in an Rsad2 knockdown lung metastasis mouse model in which mDCs lost their antitumor efficacy. Data on the CTL population further supported the results as above. Taken together, Rsad2 was an obvious and specific marker necessary for DC maturation and these findings will be clearly helpful for further understanding of DC biology.

SUBMITTER: Jang JS

PROVIDER: S-EPMC6070531 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Rsad2 is necessary for mouse dendritic cell maturation via the IRF7-mediated signaling pathway.

Jang Ji-Su JS Lee Jun-Ho JH Jung Nam-Chul NC Choi So-Yeon SY Park Soo-Yeoun SY Yoo Ji-Young JY Song Jie-Young JY Song Jie-Young JY Seo Han Geuk HG Lee Hyun Soo HS Lim Dae-Seog DS

Cell death & disease 20180801 8

Dendritic cells (DCs) are the most potent professional antigen presenting cells and inducers of T cell-mediated immunity. However, few specific markers of mature DCs (mDC) have been reported. A previous microarray analysis revealed expression of mDC-specific genes and identified Rsad2 (radical S-adenosyl methionine domain containing 2) as a candidate specific marker for DC maturation. Mouse bone marrow-derived DCs were transfected with Rsad2 siRNA and examined by flow cytometry, ELISA, western, ...[more]

PMID: 30068989

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Project description:Autoimmune hepatitis (AIH) results from an autoimmune-mediated chronic inflammatory response against liver cells. Defective self-tolerance and dysfunctional dendritic cells (DCs) play a regulatory role in AIH. Itaconate has recently attracted attention in the field of immunometabolism because of its crucial role as an anti-inflammatory metabolite that negatively regulates the inflammatory response. However, the underlying mechanism of itaconate mediation of DCs in AIH remains unclear. In this study, we found that itaconate acts as an anti-inflammatory factor in the liver. Endogenous itaconate levels were significantly increased in mice with S100-induced AIH model and correlated with upregulation of the immune-responsive gene 1 expression. However, the anti-inflammatory response from endogenously itaconate may not represent the effects exogenously-produced itaconate. We investigated the anti-inflammatory response from exogenous itaconate in S100-induced AIH, and our results showed that itaconate treatment attenuated liver histopathological damage, hepatocyte apoptosis, aminotransferase elevation, and IL-6 production in the S100-induced AIH model. In addition, Itaconate decreased glycolysis to suppress the maturation of DCs in the liver and spleen of AIH models, thereby directly regulating differentiation of Th17 and Tregs in vivo. The percentage of Th17 cells among the CD4+ population were decreased and Tregs were increased (P < 0.05). Furthermore, Itaconate-induced bone marrow-derived monocytes suppressed CD4+cells proliferation. In vitro and in vivo, we found that itaconate suppressed autophagy via activating the PI3K/AKT/mTOR signalling pathway in bone marrow-derived DCs and liver tissues. We further investigated the function of Itaconate on DC-specific mTOR-deficient mice. mTOR-deficient DCs augmented inflammatory reactions in mTORDC-/- AIH mice and induced autophagy. MHY1485 (an agonist of mTOR) and itaconate significantly alleviated the inflammatory reaction and autophagy signalling. In conclusion, itaconate ameliorate liver inflammation in S100-induced AIH mice by regulating the PI3K/AKT/mTOR pathway to decrease DCs autophagy and maturation. These results provide insight useful for treating AIH.

Dataset Information

Rsad2 is necessary for mouse dendritic cell maturation via the IRF7-mediated signaling pathway.

Publications

Rsad2 is necessary for mouse dendritic cell maturation via the IRF7-mediated signaling pathway.

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