Essential Role of mTORC1 in Self-Renewal of Murine Alveolar Macrophages

Deng, Wenhai; Yang, Jialong; Lin, Xingguang; Shin, Jin‐Wook; Gao, Jimin; Zhong, Xiao‐Ping

doi:10.4049/jimmunol.1501845

Cited by 45 publications

(31 citation statements)

References 64 publications

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“…), display a strong reduction in glucose uptake. TSC2‐deficient macrophages, which have an incremented mTORC1, increase glucose uptake in an mTORC1‐dependent manner despite a marked reduction of mTORC2–Akt activity . This might be due to the fact that mTORC2–Akt can mediate rapid relocation of Glut1 to the cell surface, while mTORC1‐mediated glucose flux probably requires a transcriptional/translational response.…”

Section: Mtor and Glycolysismentioning

confidence: 99%

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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Section: Mtor and Glycolysismentioning

confidence: 99%

mTORC1 and mTORC2 as regulators of cell metabolism in immunity

et al. 2017

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“…AM precursors develop mainly from fetal monocytes, which seed the lung prior to birth and massively expand and develop into mature macrophages in response to granulocytemacrophage colony-stimulating factor (GM-CSF) and transforming growth factor ␤ (TGF-␤) after birth (18)(19)(20). A number of factors, including PPAR-␥, mTORC1, the phosphoinositide kinase PIKfyve, and L-plastin, were also recently shown to be important in AM development and function (19,(21)(22)(23)(24). Interestingly, AM appear to be essential for protection against IAV and other respiratory viral infections (25)(26)(27)(28)(29)(30)(31).…”

mentioning

confidence: 99%

PPAR-γ in Macrophages Limits Pulmonary Inflammation and Promotes Host Recovery following Respiratory Viral Infection

Huang

Zhu

Cheon

et al. 2019

J Virol

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Alveolar macrophages (AM) play pivotal roles in modulating host defense, pulmonary inflammation, and tissue injury following respiratory viral infections. However, the transcriptional regulation of AM function during respiratory viral infections is still largely undefined. Here we have screened the expression of 84 transcription factors in AM in response to influenza A virus (IAV) infection. We found that the transcription factor PPAR-␥ was downregulated following IAV infection in AM through type I interferon (IFN)-dependent signaling. PPAR-␥ expression in AM was critical for the suppression of exaggerated antiviral and inflammatory responses of AM following IAV and respiratory syncytial virus (RSV) infections. Myeloid PPAR-␥ deficiency resulted in enhanced host morbidity and increased pulmonary inflammation following both IAV and RSV infections, suggesting that macrophage PPAR-␥ is vital for restricting severe host disease development. Using approaches to selectively deplete recruiting monocytes, we demonstrate that PPAR-␥ expression in resident AM is likely important in regulating host disease development. Furthermore, we show that PPAR-␥ was critical for the expression of wound healing genes in AM. As such, myeloid PPAR-␥ deficiency resulted in impaired inflammation resolution and defective tissue repair following IAV infection. Our data suggest a critical role of PPAR-␥ expression in lung macrophages in the modulation of pulmonary inflammation, the development of acute host diseases, and the proper restoration of tissue homeostasis following respiratory viral infections.IMPORTANCE Respiratory viral infections, like IAV and respiratory syncytial virus (RSV) infections, impose great challenges to public health. Alveolar macrophages (AM) are lung-resident immune cells that play important roles in protecting the host against IAV and RSV infections. However, the underlying molecular mechanisms by which AM modulate host inflammation, disease development, and tissue recovery are not very well understood. Here we identify that PPAR-␥ expression in AM is crucial to suppress pulmonary inflammation and diseases and to promote fast host recovery from IAV and RSV infections. Our data suggest that targeting macrophage PPAR-␥ may be a promising therapeutic option in the future to suppress acute inflammation and simultaneously promote recovery from severe diseases associated with respiratory viral infections.A cute respiratory viral infections, such as influenza A virus (IAV) and respiratory syncytial virus (RSV) infections, cause severe morbidity and mortality and are among leading causes of death in children and the elderly (1, 2). Particularly, IAV

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“…Lung macrophages are highly heterogeneous populations including alveolar macrophages (AM) and IM. Previously, an essential role of mTORC1 for AM homeostasis by regulating proliferative renewal (31) and contribution of AM to the premetastatic niche in a model of breast cancer (30) have been demonstrated. Thus, we assessed the percentages of monocytes and macrophages in naive and tumor-bearing lungs of control and Raptor cKO mice.…”

Section: Depletion Of Myeloid Cell Mtorc1 Signaling Promotes Lung Canmentioning

confidence: 99%

Tumor Microenvironment Modulates Immunological Outcomes of Myeloid Cells with mTORC1 Disruption

Ding

Sun

et al. 2019

The Journal of Immunology

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The role of the mTOR signaling pathway in different myeloid cell subsets is poorly understood in the context of tumor development. In this study, myeloid cell-specific Raptor knockout (KO) mice were used to determine the roles of mechanistic target of rapamycin complex 1 (mTORC1) in regulating macrophage function from Lewis lung carcinoma (LLC) s.c. tumors and lung tumor metastasis. We found no difference in tumor growth between conditional Raptor KO and control mice in the s.c. tumor models, although depletion of mTORC1 decreased the immunosuppressive function of tumor-associated macrophages (TAM). Despite the decreased immunosuppressive activity of TAM, M1-like TAM differentiation was impaired in the s.c. tumor microenvironment of mTORC1 conditional Raptor KO mice due to downregulated CD115 expression on macrophages. In addition, TNF-a production by mTORC1-deficient myeloid cells was also decreased in the s.c. LLC tumors. On the contrary, disruption of mTORC1 in myeloid cells promoted lung cancer metastasis. Accordingly, immunosuppressive interstitial macrophages/ metastasis-associated macrophages (CD11b + F4/80 high) were accumulated in the lungs of Raptor KO mice in the LLC lung metastasis model, leading to decreased Th1 responses. Taken together, our results demonstrate that differential tumor microenvironment dictates the immunological outcomes of myeloid cells, with mTORC1 disruption leading to different tumor growth phenotypes.

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Essential Role of mTORC1 in Self-Renewal of Murine Alveolar Macrophages

Cited by 45 publications

References 64 publications

mTORC1 and mTORC2 as regulators of cell metabolism in immunity

mTORC1 and mTORC2 as regulators of cell metabolism in immunity

PPAR-γ in Macrophages Limits Pulmonary Inflammation and Promotes Host Recovery following Respiratory Viral Infection

Tumor Microenvironment Modulates Immunological Outcomes of Myeloid Cells with mTORC1 Disruption

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