Dataset Information

MTORC1-Activated Monocytes Increase Tregs and Inhibit the Immune Response to Bacterial Infections.

ABSTRACT: The TSC1/2 heterodimer, a key upstream regulator of the mTOR, can inhibit the activation of mTOR, which plays a critical role in immune responses after bacterial infections. Monocytes are an innate immune cell type that have been shown to be involved in bacteremia. However, how the mTOR pathway is involved in the regulation of monocytes is largely unknown. In our study, TSC1 KO mice and WT mice were infected with E. coli. When compared to WT mice, we found higher mortality, greater numbers of bacteria, decreased expression of coactivators in monocytes, increased numbers of Tregs, and decreased numbers of effector T cells in TSC1 KO mice. Monocytes obtained from TSC1 KO mice produced more ROS, IL-6, IL-10, and TGF-? and less IL-1, IFN-?, and TNF-?. Taken together, our results suggest that the inhibited immune functioning in TSC1 KO mice is influenced by mTORC1 activation in monocytes. The reduced expression of coactivators resulted in inhibited effector T cell proliferation. mTORC1-activated monocytes are harmful during bacterial infections. Therefore, inhibiting mTORC1 signaling through rapamycin administration could rescue the harmful aspects of an overactive immune response, and this knowledge provides a new direction for clinical therapy.

SUBMITTER: Fang L

PROVIDER: S-EPMC5056273 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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mTORC1-Activated Monocytes Increase Tregs and Inhibit the Immune Response to Bacterial Infections.

Fang Lijun L Tu Huaijun H Guo Wei W Wang Shixuan S Xue Ting T Yang Fei F Zhang Xiaoyan X Yang Yazhi Y Wan Qian Q Shi Zhexin Z Zhan Xulong X Li Jian J

Mediators of inflammation 20160926

The TSC1/2 heterodimer, a key upstream regulator of the mTOR, can inhibit the activation of mTOR, which plays a critical role in immune responses after bacterial infections. Monocytes are an innate immune cell type that have been shown to be involved in bacteremia. However, how the mTOR pathway is involved in the regulation of monocytes is largely unknown. In our study, TSC1 KO mice and WT mice were infected with <i>E. coli</i>. When compared to WT mice, we found higher mortality, greater number ...[more]

PMID: 27746591

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Project description:The mammalian target of rapamycin (mTOR) is an evolutionarily highly conserved atypical serine/threonine protein kinase, which regulates cell growth, proliferation, apoptosis, autophagy, and metabolism. As a regulatory protein, Raptor is awfully important for the stability and function of mTOR complex 1 (mTORC1). However, the studies about how Raptor/mTORC1 participates in and regulates immune response in lower vertebrates are still limited. In this study, we investigated the regulation of immune response by the Raptor/mTORC1 signaling pathway in rockfish Sebastes schlegelii. Sebastes schlegelii Raptor (Ss-Raptor) is a highly conserved protein during the evolution, in both primary and tertiary structure. Ss-Raptor mRNA was widely distributed in various tissues of rockfish and has a relative higher expression in spleen and blood. After infected by Micrococcus luteus or Listonella anguillarum, mRNA expression of Ss-Raptor rapidly increased within 48 h. Once Raptor/mTORC1 signaling was blocked by rapamycin, expression of the pro-inflammatory cytokines IL-1β and IL-8 was severely impaired, suggesting potential regulatory role of Raptor/mTORC1 signaling in the innate immune response of rockfish. In addition, Raptor/mTORC1 pathway participated in lymphocyte activation of rockfish through promoting 4EBP1 and S6 phosphorylation. Inhibition of Raptor/mTORC1 signaling crippled the lymphocyte expansion during primary adaptive immune response, manifesting by the decrease of lymphoid organ weight and lymphocyte numbers. More importantly, inhibition of Raptor/mTORC1 signaling impaired the lymphocyte mediated cytotoxic response, and made the fish more vulnerable to the bacterial infection. Together, our results suggested that Raptor and its tightly regulated mTORC1 signaling acts as modulatory center to regulate both innate and lymphocyte-mediated adaptive immune response during bacterial infection. This research has shed new light on regulatory mechanism of teleost immune response, and provide helpful evidences to understand the evolution of immune system.

Project description:OBJECTIVE:Angiotensin II type 1 receptor (AT1) blockers (ARBs) reduce the bacterial endotoxin lipopolysaccharide (LPS)-induced innate immune response in human circulating monocytes expressing few AT1. To clarify the mechanisms of anti-inflammatory effects of ARBs with different peroxisome proliferator-activated receptor-? (PPAR?)-activating potencies, we focused our study on telmisartan, an ARB with the highest PPAR?-stimulating activity. METHODS:Human circulating monocytes and monocytic THP-1 (human acute monocytic leukemia cell line) cells were exposed to 50?ng/ml LPS with or without pre-incubation with telmisartan. AT1 mRNA and protein expressions were determined by real-time PCR and membrane receptor binding assay, respectively. The expression of pro-inflammatory factors was determined by real-time PCR, western blot analysis and ELISA. PPAR? activation was measured by electrophoretic mobility shift assay and its role was determined by pharmacological inhibition and PPAR? gene silencing. RESULTS:In human monocytes, telmisartan significantly attenuated the LPS-induced expression of pro-inflammatory factors, the release of pro-inflammatory cytokines and prostaglandin E2, nuclear factor-?B activation and reactive oxygen species formation. In THP-1 cells, telmisartan significantly reduced LPS-induced tumor necrosis factor-?, inhibitor of ?B-?, monocyte chemotactic protein-1 (MCP-1) and lectin-like oxidized low-density lipoprotein receptor-1 gene expression and MCP-1-directed migration. Telmisartan also stimulated the expression of the PPAR? target genes cluster of differentiation 36 and ATP-binding cassette subfamily G member 1 in monocytes. The anti-inflammatory effects of telmisartan were prevented by both PPAR? antagonism and PPAR? gene silencing. Anti-inflammatory effects of ARBs correlated with their PPAR? agonist potency. CONCLUSION:Our observations demonstrate that in human monocytes, ARBs inhibit the LPS-induced pro-inflammatory response to a major extent through the PPAR? activation pathway and may be beneficial for the treatment of cardiovascular and metabolic disorders in which inflammation plays a major role.

Dataset Information

MTORC1-Activated Monocytes Increase Tregs and Inhibit the Immune Response to Bacterial Infections.

Publications

mTORC1-Activated Monocytes Increase Tregs and Inhibit the Immune Response to Bacterial Infections.

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