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Taurodeoxycholate Increases the Number of Myeloid-Derived Suppressor Cells That Ameliorate Sepsis in Mice.

ABSTRACT: Bile acids (BAs) control metabolism and inflammation by interacting with several receptors. Here, we report that intravenous infusion of taurodeoxycholate (TDCA) decreases serum pro-inflammatory cytokines, normalizes hypotension, protects against renal injury, and prolongs mouse survival during sepsis. TDCA increases the number of granulocytic myeloid-derived suppressor cells (MDSCLT) distinctive from MDSCs obtained without TDCA treatment (MDSCL) in the spleen of septic mice. FACS-sorted MDSCLT cells suppress T-cell proliferation and confer protection against sepsis when adoptively transferred better than MDSCL. Proteogenomic analysis indicated that TDCA controls chromatin silencing, alternative splicing, and translation of the immune proteome of MDSCLT, which increases the expression of anti-inflammatory molecules such as oncostatin, lactoferrin and CD244. TDCA also decreases the expression of pro-inflammatory molecules such as neutrophil elastase. These findings suggest that TDCA globally edits the proteome to increase the number of MDSCLT cells and affect their immune-regulatory functions to resolve systemic inflammation during sepsis.

SUBMITTER: Chang S

PROVIDER: S-EPMC6153344 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Publications

Taurodeoxycholate Increases the Number of Myeloid-Derived Suppressor Cells That Ameliorate Sepsis in Mice.

Chang Sooghee S Kim Youn-Hee YH Kim Young-Joo YJ Kim Young-Woo YW Moon Sungyoon S Lee Yong Yook YY Jung Jin Sun JS Kim Youngsoo Y Jung Hi-Eun HE Kim Tae-Joo TJ Cheong Taek-Chin TC Moon Hye-Jung HJ Cho Jung-Ah JA Kim Hang-Rae HR Han Dohyun D Na Yirang Y Seok Seung-Hyeok SH Cho Nam-Hyuk NH Lee Hai-Chon HC Nam Eun-Hee EH Cho Hyosuk H Choi Murim M Minato Nagahiro N Seong Seung-Yong SY

Frontiers in immunology 20180918

Bile acids (BAs) control metabolism and inflammation by interacting with several receptors. Here, we report that intravenous infusion of taurodeoxycholate (TDCA) decreases serum pro-inflammatory cytokines, normalizes hypotension, protects against renal injury, and prolongs mouse survival during sepsis. TDCA increases the number of granulocytic myeloid-derived suppressor cells (MDSC<sub>LT</sub>) distinctive from MDSCs obtained without TDCA treatment (MDSC<sub>L</sub>) in the spleen of septic mic ...[more]

PMID: 30279688

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Project description:BackgroundPeriodontitis is closely associated with the pathogenesis of Alzheimer's disease (AD). Porphyromonas gingivalis (Pg), the keystone periodontal pathogen, has been reported in our recent study to cause immune-overreaction and induce cognitive impairment. Monocytic myeloid-derived suppressor cells (mMDSCs) possess potent immunosuppressive function. It is unclear whether mMDSCs-mediated immune homeostasis is impaired in AD patients with periodontitis, and whether exogenous mMDSCs could ameliorate immune-overreaction and cognitive impairment induced by Pg.MethodsTo explore the influence of Pg on cognitive function, neuropathology and immune balance in vivo, 5xFAD mice were treated with live Pg by oral gavage, three times a week for 1 month. The cells of peripheral blood, spleen and bone marrow from 5xFAD mice were treated with Pg to detect the proportional and functional alterations of mMDSCs in vitro. Next, exogenous mMDSCs were sorted from wild-type healthy mice and intravenously injected into 5xFAD mice that were infected with Pg. We used behavioral tests, flow cytometry and immunofluorescent staining to evaluate whether exogenous mMDSCs could ameliorate the cognitive function, immune homeostasis and reduce neuropathology exacerbated by Pg infection.ResultsPg exacerbated cognitive impairment in 5xFAD mice, with the deposition of amyloid plaque and increased number of microglia in the hippocampus and cortex region. The proportion of mMDSCs decreased in Pg-treated mice. In addition, Pg reduced the proportion and the immunosuppressive function of mMDSCs in vitro. Supplement of exogenous mMDSCs improved the cognitive function, and enhanced the proportions of mMDSCs and IL-10+ T cells of 5xFAD mice infected with Pg. At the same time, supplement of exogenous mMDSCs increased the immunosuppressive function of endogenous mMDSCs while decreased the proportions of IL-6+ T cells and IFN-γ+ CD4+ T cells. In addition, the deposition of amyloid plaque decreased while the number of neurons increased in the hippocampus and cortex region after the supplement of exogenous mMDSCs. Furthermore, the number of microglia increased with an increase in the proportion of M2 phenotype.ConclusionsPg can reduce the proportion of mMDSCs, induce immune-overreaction, and exacerbate the neuroinflammation and cognitive impairment in 5xFAD mice. Supplement of exogenous mMDSCs can reduce the neuroinflammation, immune imbalance and cognitive impairment in 5xFAD mice infected with Pg. These findings indicate the mechanism of AD pathogenesis and Pg-mediated promotion of AD, and provide a potential therapeutic strategy for AD patients.

Dataset Information

Taurodeoxycholate Increases the Number of Myeloid-Derived Suppressor Cells That Ameliorate Sepsis in Mice.

Publications

Taurodeoxycholate Increases the Number of Myeloid-Derived Suppressor Cells That Ameliorate Sepsis in Mice.

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