TSC1 controls macrophage polarization to prevent inflammatory disease

Zhu, Linnan; Yang, Tao; Li, Longjie; Sun, Lina; Hou, Yuzhu; Hu, Xuelian; Zhang, Lianjun; Tian, Hua; Zhao, Qingjie; Peng, Jiao; Zhang, Hongbing; Wang, Ruoyu; Yang, Zhongzhou; Zhang, Lianfeng; Zhao, Yong

doi:10.1038/ncomms5696

Cited by 266 publications

(260 citation statements)

References 61 publications

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“…These findings indicate that activated mTOR may limit pro-inflammatory responses. On the contrary, other studies indicated that TSC1-deficient macrophages produced elevated pro-inflammatory cytokines including TNF-a, IL12p40, and IL-6 in response to multiple TLR ligands 19,23 . Moreover, TSC1-deficient BMDMs treated by LPS secreted more of the pro-inflammatory cytokines such as IL-6 and TNF-a but less of the anti-inflammatory cytokine IL-10 24 .…”

Section: Introductionmentioning

confidence: 85%

“…In addition, TSC1-deficient macrophages in response to LPS stimulation produce elevated pro-inflammatory cytokines, such as TNF-a, IL-12, and IL-6 19,23,24 . The reasons for this inconsistency are unclear, possibly due to the different cell types and duration of mTOR inhibition with Rapa or mTOR deletion used in these studies.…”

Section: Discussionmentioning

confidence: 99%

“…Scramble and TSC1 shRNA cells were stimulated with LPS Figure 4C). We have demonstrated that increased p-ERK in TSC1 KO macrophages was dependent on the loss of TSC2 GTPase-activating protein (GAP) activity 23 . However, blocking ERK and JNK activity (PD98059 and SP600125, respectively) significantly inhibited pro-IL-1b expression in WT and TSC1 KO macrophages (Supplementary Figure 5).…”

Section: Tsc1 Deficiency Does Not Inhibit Activation Of Mapks and Nf-mentioning

confidence: 99%

“…However, TSC1 shRNA cells showed similar phosphorylation levels of P38 and JNK relative to scramble cells after stimulation with LPS ( Figure 4C). Interestingly, increased p-ERK was observed in TSC1 KO macrophages due to loss of TSC2 GTPase-activating protein (GAP) activity 23 . However, pro-IL-1b expression was upregulated by ERK and JNK in macrophages (Supplementary Figure 5).…”

Section: Tsc1 Regulates Il-1b T Yang Et Almentioning

confidence: 99%

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TSC1 controls IL-1β expression in macrophages via mTORC1-dependent C/EBPβ pathway

et al. 2015

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The tuberous sclerosis complex 1 (TSC1) is a tumor suppressor that inhibits the mammalian target of rapamycin (mTOR), which serves as a key regulator of inflammatory responses after bacterial stimulation in monocytes, macrophages, and primary dendritic cells. Previous studies have shown that TSC1 knockout (KO) macrophages produced increased inflammatory responses including tumor necrosis factor-a (TNF-a) and IL-12 to pro-inflammatory stimuli, but whether and how TSC1 regulates pro-IL-1b expression remains unclear. Here using a mouse model in which myeloid lineage-specific deletion of TSC1 leads to constitutive mTORC1 activation, we found that TSC1 deficiency resulted in impaired expression of pro-IL-1b in macrophages following lipopolysaccharide stimulation. Such decreased pro-IL-1b expression in TSC1 KO macrophages was rescued by reducing mTORC1 activity with rapamycin or deletion of mTOR. Rictor deficiency has no detectable effect on pro-IL-1b synthesis, suggesting that TSC1 positively controls pro-IL-1b expression through mTORC1 pathway. Moreover, mechanism studies suggest that mTORC1-mediated downregulation of the CCAAT enhancer-binding protein (C/EBPb) critically contributes to the defective pro-IL-1b expression. Overall, these findings highlight a critical role of TSC1 in regulating innate immunity by control of the mTOR1-C/EBPb pathway. Cellular & Molecular Immunology

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Section: Introductionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Section: Tsc1 Deficiency Does Not Inhibit Activation Of Mapks and Nf-mentioning

confidence: 99%

Section: Tsc1 Regulates Il-1b T Yang Et Almentioning

confidence: 99%

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TSC1 controls IL-1β expression in macrophages via mTORC1-dependent C/EBPβ pathway

et al. 2015

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“…However, the expression of Foxp3 control immune responses by their suppressive activity [108]. GM-CSF, TLR ligands and IL-4 promote activation of mTORC1 (figure :10) and mTORC2 (figure :11) in the immune cells, more specifically DCs, neutrophils, monocytes and macrophages [109]- [120]. The activation of mTORC1 and mTORC2 controls a wide range of basic cellular processes such as protein translation and synthesis, cell growth, metabolism and anabolic processes.…”

Section: B Cytoscapementioning

confidence: 99%

Untitled

2017

RJLBPCS

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ABSTRACT:One of the many challenges of bioinformatics, now a day; is the integration of biological data.The establishment of large quantities of data concerning the differentially expressed genes during infection with an intracellular pathogen requires the implementation of integration strategies to gather all the data and therefore a better understanding of the functioning of the Intracellular infection. This work aims to exploit the bioinformatics approach, to provide a new interpretation of the data available in the literature as well as databases on the effect of intracellular infection, cases of the Leishmania parasite, on the host. A total of 30 genes expressed differently from a Leishmania parasite infection were used for functional analysis using the bioinformatics tool. The latter provides rapid assessment of signaling and metabolic pathways, molecular networks and biological processes that are more significantly disrupted in a data set of interest. Bioinformatics analysis revealed that apoptosis, cytokine production, and signaling were altered following infection with the Leishmania parasite. The genes of IL-10, IL-4, IL-6, SOD1, EIF2AK2, NF-kB and PI3K/akt were most activated after Infection by the Leishmania parasite. The results suggest that the Leishmania parasite reverses immune and inflammatory responses, meaning the ability to induce programmed cell death and microbicidal functions of macrophages such as inhibition of nitric oxide (NO), And the functions of the inducible cytokines of macrophages. Analyzing and interpreting data using the bioinformatics approach helps to unlock knowledge buried in experimental data by quickly identifying links, mechanisms, functions and main pathways to move beyond Statistical analysis to new biological analyzes.

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mTORC1 and mTORC2 as regulators of cell metabolism in immunity

et al. 2017

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The mechanistic target of rapamycin (mTOR) pathway is an evolutionarily conserved signaling pathway that senses intra-and extracellular nutrients, growth factors, and pathogen-associated molecular patterns to regulate the function of innate and adaptive immune cell populations. In this review, we focus on the role of the mTOR complex 1 (mTORC1) and mTORC2 in the regulation of the cellular energy metabolism of these immune cells to regulate and support immune responses. In this regard, mTORC1 and mTORC2 generally promote an anabolic response by stimulating protein synthesis, glycolysis, mitochondrial functions, and lipid synthesis to influence proliferation and survival, effector and memory responses, innate training and tolerance as well as hematopoietic stem cell maintenance and differentiation. Deactivation of mTOR restores cell homeostasis after immune activation and optimizes antigen presentation and memory T-cell generation. These findings show that the mTOR pathway integrates spatiotemporal information of the environmental and cellular energy status by regulating cellular metabolic responses to guide immune cell activation. Elucidation of the metabolic control mechanisms of immune responses will help to generate a systemic understanding of the immune system.

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TSC1 controls macrophage polarization to prevent inflammatory disease

Cited by 266 publications

References 61 publications

TSC1 controls IL-1β expression in macrophages via mTORC1-dependent C/EBPβ pathway

TSC1 controls IL-1β expression in macrophages via mTORC1-dependent C/EBPβ pathway

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mTORC1 and mTORC2 as regulators of cell metabolism in immunity

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