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  • Review Article
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Activation of mTOR (mechanistic target of rapamycin) in rheumatic diseases

Key Points

  • The mechanistic target of rapamycin (mTOR) is a serine/threonine kinase that regulates growth, proliferation, survival and autophagy in a cell-type-specific manner

  • mTOR forms two interacting complexes, mTORC1 and mTORC2

  • mTORC1 drives the proinflammatory expansion of T helper (TH) type 1, TH17, and CD4CD8 double-negative T cells, which collectively orchestrate the pathogenesis of autoimmune diseases

  • mTORC1 contributes to erosive arthritis by mediating the proliferation of fibroblasts-like synoviocytes and osteoclasts, and contributes to osteoarthritis by restraining autophagy in chondrocytes

  • Blockade of the mTOR pathway offers new treatments and prevention strategies for rheumatic diseases

Abstract

Mechanistic target of rapamycin (mTOR, also known as mammalian target of rapamycin) is a ubiquitous serine/threonine kinase that regulates cell growth, proliferation and survival. These effects are cell-type-specific, and are elicited in response to stimulation by growth factors, hormones and cytokines, as well as to internal and external metabolic cues. Rapamycin was initially developed as an inhibitor of T-cell proliferation and allograft rejection in the organ transplant setting. Subsequently, its molecular target (mTOR) was identified as a component of two interacting complexes, mTORC1 and mTORC2, that regulate T-cell lineage specification and macrophage differentiation. mTORC1 drives the proinflammatory expansion of T helper (TH) type 1, TH17, and CD4CD8 (double-negative, DN) T cells. Both mTORC1 and mTORC2 inhibit the development of CD4+CD25+FoxP3+ T regulatory (TREG) cells and, indirectly, mTORC2 favours the expansion of T follicular helper (TFH) cells which, similarly to DN T cells, promote B-cell activation and autoantibody production. In contrast to this proinflammatory effect of mTORC2, mTORC1 favours, to some extent, an anti-inflammatory macrophage polarization that is protective against infections and tissue inflammation. Outside the immune system, mTORC1 controls fibroblast proliferation and chondrocyte survival, with implications for tissue fibrosis and osteoarthritis, respectively. Rapamycin (which primarily inhibits mTORC1), ATP-competitive, dual mTORC1/mTORC2 inhibitors and upstream regulators of the mTOR pathway are being developed to treat autoimmune, hyperproliferative and degenerative diseases. In this regard, mTOR blockade promises to increase life expectancy through treatment and prevention of rheumatic diseases.

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Figure 1: mTOR pathway activation.
Figure 2: mTOR-mediated lineage specification in T cells.
Figure 3: Cell type-specific mTOR pathway activation in rheumatic diseases.

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Acknowledgements

The author's research work is supported in part by grants AI 048079 and AI 072648 from the National Institutes of Health and the Central New York Community Foundation, and Investigator-Initiated Research Grant P0468X1-4470/WS1234172 from Pfizer.

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Perl, A. Activation of mTOR (mechanistic target of rapamycin) in rheumatic diseases. Nat Rev Rheumatol 12, 169–182 (2016). https://doi.org/10.1038/nrrheum.2015.172

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