Mammalian target of rapamycin activation underlies HSC defects in autoimmune disease and inflammation in mice

Chen, Chong; Liu, Yu; Liu, Yang; Zheng, Pan

doi:10.1172/jci43873

Cited by 97 publications

(69 citation statements)

References 34 publications

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“…This is of interest, as bone marrow dysfunctions resulting in pancytopenia-related comorbidities are common not only in patients with AIDS but also in patients treated for autoimmune diseases. Both patient groups have increased susceptibility to even low-grade Pneumocystis lung infection which might promote deviated systemic innate immune responses that may also hamper hematopoiesis (4,(62)(63)(64)(65).…”

Section: Discussionmentioning

confidence: 99%

“…These data strongly suggested that B cells may influence the outcome of the systemic inflammatory effects of Pneumocystis lung infection by either directly modulating the innate immune pathways initiated in the lung or by providing regulatory functions that interfere downstream of specific inflammatory pathways. Although hematopoiesis is stimulated by inflammatory signals intended to promote cellular maturation and mobilize inflammatory cells to the site of infection (reviewed in references 68 and 69), exuberant inflammatory stimuli can be harmful to hematopoietic stem cell functions in part by the induction of functional senescence as a result of proliferative exhaustion (63,70). However, the mechanisms that balance these effects on hematopoiesis are still poorly defined, and Consistent with this observation, B cells with regulatory, immune suppressive activity (Breg) have been defined within both follicular and marginal zone cell populations (reviewed in references 71 and 72).…”

Section: Discussionmentioning

confidence: 99%

“…Type I IFN responses and B cell functions also decline during aging (98)(99)(100)(101), resulting in a latent stage of immune suppression and susceptibility to even low-grade Pneumocystis infection (102). Under any of these conditions, systemic inflammation is common, and bone marrow dysfunctions are reported often without a clear pathogenic link (63,64,(103)(104)(105)(106)(107)(108)(109)(110).…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

B Cells Modulate Systemic Responses to Pneumocystis murina Lung Infection and Protect On-Demand Hematopoiesis via T Cell-Independent Innate Mechanisms when Type I Interferon Signaling Is Absent

et al. 2015

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HIV infection results in a complex immunodeficiency due to loss of CD4؉ T cells, impaired type I interferon (IFN) responses, and B cell dysfunctions causing susceptibility to opportunistic infections such as Pneumocystis murina pneumonia and unexplained comorbidities, including bone marrow dysfunctions. Type I IFNs and B cells critically contribute to immunity to Pneumocystis lung infection. We recently also identified B cells as supporters of on-demand hematopoiesis following Pneumocystis infection that would otherwise be hampered due to systemic immune effects initiated in the context of a defective type I IFN system. While studying the role of type I IFNs in immunity to Pneumocystis infection, we discovered that mice lacking both lymphocytes and type I IFN receptor (IFrag Pneumocystis is a ubiquitous extracellular pulmonary fungal pathogen with strict species specificity. It is likely contracted via airborne transmission from often transiently infected individuals and commonly causes few or unspecific symptoms in otherwise healthy individuals leading to immunity (reviewed in references 1 and 2). However, Pneumocystis can cause severe and progressive interstitial pneumonia in patients with impaired acquired immunity with mortality rates up to 60% (3). While the total number of functional CD4 ϩ T cells critically determines increased susceptibility to Pneumocystis lung infection, patients with B cell defects are also at risk. In this regard, Pneumocystis pneumonia (PCP) is an AIDSdefining condition during HIV disease progression and commonly occurs when CD4 ϩ T cell counts drop below 200 cells/l (4). Furthermore, immune suppressive and cell ablative therapy following solid-organ transplantation, autoimmunity, or cancer treatment reduce CD4 ϩ T cell and/or B cell numbers and impair functions in non-HIV patients (reviewed in references 5 and 6). Drug regimens that predispose to severe Pneumocystis infections include high-dose glucocorticoid and B cell ablative treatments with rituximab (7-11). In addition, low-grade Pneumocystis infection is found in patients with potentially subtle immune suppressions such as young infants, HIV-positive patients receiving HAART (highly active antiretroviral therapy), or patients receiving low-dose and inhaled glucocorticoids (12)(13)(14). This can promote bronchial hyperreactivity, is associated with sudden infant death syndrome (SIDS) and exacerbation of chronic obstructive lung diseases (15)(16)(17)(18)(19).Pneumocystis colonization also intensifies signs of systemic inflammation (20, 21). Thus, Pneumocystis may act as a profound comorbidity factor that may also enhance secondary systemic disease manifestations associated with chronic pulmonary diseases and HIV infection such as osteoporosis or bone marrow dysfunctions (22-28). Immunity to Pneumocystis requires the presence of functional CD4 ϩ T cells to stimulate antigen-specific immune globulin production by B cells and macrophage-mediated phagocytosis (4,(29)(30)(31)(32)(33)(34)(35)(36)(37)(38). In addition, early innate t...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

B Cells Modulate Systemic Responses to Pneumocystis murina Lung Infection and Protect On-Demand Hematopoiesis via T Cell-Independent Innate Mechanisms when Type I Interferon Signaling Is Absent

et al. 2015

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“…LPS activates mTOR in phagocytes [1,20,53], bone marrow cells [9] and HL-1 cells (a cardiomyocyte cell line) [49]; however, the role of mTOR in pro-inflammatory cytokine expression is celltype specific. For example, rapamycin, an mTOR inhibitor decreased the production of pro-inflammatory cytokines such as IL-12 and TNF-a in dendritic cells [20].…”

Section: Discussionmentioning

confidence: 99%

“…Studies have shown that mTOR contributes to cardiac hypertrophy [11,35] and ventricular remodeling after myocardial infarction [6]. LPS activates mTOR [1,9,20,53], however, its role in proinflammatory cytokine expression during sepsis remains controversial. For example, mTOR activation by LPS promotes TNF-a and interleukin-12 expression in monocyte-derived dendritic cells [20].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Na/K-ATPase promotes myocardial tumor necrosis factor-alpha protein expression and cardiac dysfunction via calcium/mTOR signaling in endotoxemia

Zhang

et al. 2012

Basic Res Cardiol

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Tumor necrosis factor-α (TNF-α) is a major pro-inflammatory cytokine that causes cardiac dysfunction during sepsis. Na/K-ATPase regulates intracellular Ca(2+), which activates mammalian target of rapamycin (mTOR), a regulator of protein synthesis. The aim of this study was to investigate the role of Na/K-ATPase/mTOR signaling in myocardial TNF-α expression during endotoxemia. Results showed that treatment with LPS decreased Na/K-ATPase activity in the myocardium in vivo and in cultured neonatal cardiomyocytes. Inhibition of Na/K-ATPase by ouabain enhanced LPS-induced myocardial TNF-α protein production, but had no effect on TNF-α mRNA expression. More importantly, ouabain further decreased in vivo cardiac function in endotoxemic mice, which was blocked by etanercept, a TNF-α antagonist. LPS-induced reduction in Na/K-ATPase activity was prevented by inhibition of PI3K, Rac1 and NADPH oxidase using LY294002, a dominant-negative Rac1 adenovirus (Ad-Rac1N17) and apocynin, respectively. To assess the role of Rac1 in Ca(2+) handling, Ca(2+) transients in adult cardiomyocytes from cardiomyocyte-specific Rac1 knockout (Rac1(CKO)) and wild-type (WT) mice were determined. LPS increased intracellular Ca(2+) in WT but not in Rac1(CKO) cardiomyocytes. Furthermore, LPS rapidly increased mTOR phosphorylation in cardiomyocytes, which was blocked by Rac1N17 and an inhibitor of calmodulin-dependent protein kinases (CaMKs) KN93, but enhanced by ouabain. Rapamycin, an inhibitor of mTOR suppressed TNF-α protein levels without any significant effect on its mRNA expression or global protein synthesis. In conclusion, myocardial Na/K-ATPase activity is inhibited during endotoxemia via PI3K/Rac1/NADPH oxidase activation. Inhibition of Na/K-ATPase activates Ca(2+)/CaMK/mTOR signaling, which promotes myocardial TNF-α protein production and cardiac dysfunction during endotoxemia.

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AKT hyperactivation confers a Th1 phenotype in thymic Treg cells deficient in TGF‐β receptor II signaling

Liu

Sun

et al. 2013

Eur J Immunol

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The generation of CD4 + Foxp3 + Treg cells in the thymus is crucial for immune homeostasis and self-tolerance. Recent studies have shown Treg-cell plasticity when Th-related transcriptional factors and cytokines are present. However, the mechanisms that maintain the stability of Treg cells are poorly understood. Here, using mice with a T-cell-specific deletion of the transforming growth factor-β receptor 2 (Tgfbr2 −/− mice), we identify the restriction of AKT activation as a key event for the control of Treg-cell stability in Th1 inflammation. AKT regulation was evident in thymic CD4 + Foxp3 + Treg cells before they egressed to peripheral tissues. CD4 + Foxp3 + thymocytes from mice with the Tgfbr2 deletion expressed high levels of CXCR3 and T-bet, and produced IFN-γ and TNF-α. Thymic Tgfbr2 −/− Treg cells also showed an increase in the activation of AKT pathway. Enhanced AKT activity induced the expression of IFN-γ both in natural and inducible Treg cells. Inhibition of AKT activity markedly attenuated the expression of IFN-γ and TNF-α in thymic Tgfbr2 −/− Treg cells in vivo. In addition, mixed bone marrow transplantation showed that TGF-β signaling maintained Treg-cell stability in an intrinsic manner. Our results demonstrate that AKT hyperactivation contributes to the conversion of Treg cells to a Th1 phenotype.Keywords: AKT r Stability r TGF-β r Thymus r Treg cells Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionNatural CD4 + CD25 + Treg cells play an important role in maintaining self-tolerance and preventing autoimmune diseases and inflammation [1][2][3][4]. Treg cells are produced mainly in the thymus and express the transcription factor Foxp3, which is essential for the generation and regulatory function of Treg cells [5][6][7][8].CD4 + Foxp3 + Treg cells are heterogeneous in the phenotype and function under certain pathogenic conditions. Treg cells can Correspondence: Prof. Yongzhong Liu e-mail: liuyzg@shsci.org adjust themselves appropriately in the transcriptional program of T-effector (Teff) cell-related molecules in different inflammatory settings, to optimize the selective suppression of T cells [9][10][11]. Several studies have shown that together with alterations of Foxp3 expression, Treg cells have the potential for conversion to Th1, Th2, Th17 Teff cells as well as follicular helper T cells, and that the diversity in functional Treg-cell reprogramming may depend on the different types of inflammation [6,[12][13][14][15][16][17][18][19][20][21]. Recent studies demonstrate that Foxp3 + Treg cells can be converted to IFN-γ-producing cells or IL-17-producing cells even without loss of Foxp3 expression [22][23][24][25][26]. The heterogeneity of Treg cells is actively debated and is important for the immune homeostasis and development of diseases. By tracking the fate of Treg cells in vivo, Rubtsov et al. [27] 522Yun Liu et al. Eur. J. Immunol. 2014. 44: 521-532 both physiologic and inflammatory conditions. Miyao et al...

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Mammalian target of rapamycin activation underlies HSC defects in autoimmune disease and inflammation in mice

Cited by 97 publications

References 34 publications

B Cells Modulate Systemic Responses to Pneumocystis murina Lung Infection and Protect On-Demand Hematopoiesis via T Cell-Independent Innate Mechanisms when Type I Interferon Signaling Is Absent

B Cells Modulate Systemic Responses to Pneumocystis murina Lung Infection and Protect On-Demand Hematopoiesis via T Cell-Independent Innate Mechanisms when Type I Interferon Signaling Is Absent

Inhibition of Na/K-ATPase promotes myocardial tumor necrosis factor-alpha protein expression and cardiac dysfunction via calcium/mTOR signaling in endotoxemia

AKT hyperactivation confers a Th1 phenotype in thymic Treg cells deficient in TGF‐β receptor II signaling

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