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Weichhart Lab

Thomas Weichhart, Assoc. Prof. Priv. Doz. Mag. Dr.

Geneticist

Tel.: +43 (0)1 40160-56515
E-Mail: thomas.weichhart@meduniwien.ac.at

Regulation of innate immune responses by the mTOR pathway

The innate myeloid immune system is a complex network of cells that protect against disease by identifying and killing pathogens and tumor cells, but it is also implicated in homeostatic mechanisms like tissue remodeling and wound healing. Myeloid phagocytes such as monocytes, macrophages, or dendritic cells are at the basis of controlling these immune responses in all tissues of the body. Our group has shown previously that the mechanistic target of rapamycin (mTOR) pathway is crucially implicated in these innate reactions and serves as a decision maker to control the cellular response to pathogens by regulating the expression of inflammatory mediators such as cytokines, chemokines or interferons.
The main focus of our group is to study the molecular mechanisms of how the mTOR pathway influences innate immune activation in macrophages and dendritic cells induced by pathogens or environmental signals and its consequences for the adaptive immune response. We study how inhibition of mTOR, which is an established therapy in basic organ transplantation and cancer, modulates the inflammatory response and how the mTOR pathway incorporates environmental and nutritional signals to regulate host immunity and tissue homeostasis. These processes are studied by biochemical and molecular approaches and in mouse models in vivo by analyzing mice with tissue-specific knockouts for certain molecules of the mTOR pathway.

Fig. 1: Inhibition of mTOR by rapamycin protects mice against a Listeria monocytogenes (L.m.) infection. Reduced granulomatous lesions in the liver of rapamycin-treated mice (stained with H&E). Rapamycin reduces the expression of the anti-inflammatory cytokine IL-10 in the spleen of L.m.-infected mice.

Linke M, Pham HT, Katholnig K, Schnöller T, Miller A, Demel F, Schütz B, Rosner M, Kovacic B, Sukhbaatar N, Niederreiter B, Blüml S, Kuess P, Sexl V, Müller M, Mikula M, Weckwerth W, Haschemi A, Susani M, Hengstschläger M, Gambello MJ, Weichhart T. Chronic signaling via the metabolic checkpoint kinase mTORC1 induces macrophage granuloma formation and marks sarcoidosis progression. Nat Immunol. 2017 Mar;18(3):293-302.

 

Sukhbaatar N, Hengstschläger M, Weichhart T. mTOR-Mediated Regulation of Dendritic Cell Differentiation and Function. Trends Immunol. 2016 Nov;37(11):778-789

 

Weichhart T, Hengstschläger M, Linke M; Regulation of innate immune cell function by mTOR. Nat Rev Immunol. 2015 Sep 25;15(10):599-614.

 

Fritsch SD, Weichhart T. Effects of Interferons and Viruses on Metabolism. Front Immunol. 2016 Dec 21;7:630.

 

Üstün S, Lassnig C, Preitschopf A, Mikula M, Müller M, Hengstschläger M, Weichhart T. Effects of the mTOR inhibitor everolimus and the PI3K/mTOR inhibitor NVP-BEZ235 in murine acute lung injury models. Transpl Immunol. 2015 Sep;33(1):45-50.

 

Katholnig K, Kaltenecker CC, Hayakawa H, Rosner M, Lassnig C, Zlabinger GJ, Gaestel M, Müller M, Hengstschläger M, Hörl WH, Park JM, Säemann MD, Weichhart T; p38? Senses Environmental Stress To Control Innate Immune Responses via Mechanistic Target of Rapamycin. J Immunol. 2013 Feb 15;190(4):1519-27.