Activation of mTOR (mechanistic target of rapamycin) in 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 CD4(-)CD8(-) (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.

Figure 1. mTOR pathway activation

Mechanistic target of rapamycin (mTOR) is regulated by metabolic cues, primarily glucose and amino acids, as well as by growth factors, hormones and cytokines. Glucose and amino acids enter cells via surface receptors such as glucose transporter type 1, erythrocyte/brain (GLUT1) or glucose transporter type 4, insulin-responsive (GLUT4) and CD98, respectively. Growth factors stimulate tyrosine kinase receptors (TKRs), which are activated through phosphorylation of tyrosine residues. In turn, TKR signals are transmitted to mTOR through phosphati-dylinositide 3-kinase (PI3K), phosphoinositide-dependent kinase-1 (PDK1) and RAC serine/threonine-protein kinase (AKT). Signalling through sphingosine 1-phosphate receptor 1 (S1P₁) also activates mTOR complex 1 (mTORC1) via PI3K. Downstream, AKT phosphorylates mTOR, which forms two interacting complexes, mTORC1 and mTORC2. mTORC1 is composed of mTOR, regulatory-associated protein of TOR (raptor), TORC subunit LST8 (LST8), DEP-domain-containing mTOR-interacting protein (deptor) and proline-rich AKT1 substrate 1 (AKT1S1). mTORC2 is comprised of mTOR, rapa-mycin-insensitive companion of mTOR (rictor), stress-activated protein kinase interacting protein 1 (mSIN1, also known as TORC2 subunit MAPKAP1), protein observed with rictor-1 (protor-1), deptor and LST8. mTORC1 integrates growth signals reflecting the availability of nutrients and energy to promote either proliferation when conditions are favourable or autophagy when conditions are unfavorable; mTORC2 promotes cellular survival by activating AKT. Pharmacologically targetable checkpoints are highlighted in yellow. 4E–BP1, eukaryotic translation initiation factor 4E–binding protein 1; AMBRA1, activating molecule in BECN1-regulated autophagy protein 1; AMPK, 5’-AMP-activated protein kinase; Arf1, ADP-ribosylation factor 1; FKBP12, peptidyl-prolyl cis-trans isomerase FKBP12; HIF1α, hypoxia-inducible factor 1α; NAC, N-acetylcysteine; PKCα, protein kinase C α type; PTEN, phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN; RAPA, rapamycin; Rag-A/B, Ras-related GTP-binding protein A/B; ROI, reactive oxygen intermediate; S6K, ribosomal protein S6 kinase; SREBP1, sterol regulatory element-binding protein 1; STAT3, signal transducer and activator of transcription 3.

Figure 2. mTOR-mediated lineage specification in T cells

Mechanistic target of rapamycin (mTOR) is a sensor of metabolic stress and integrator of environmental cues. Activation of mTOR complex 1 (mTORC1) is triggered by oxidative stress, amino-acid levels and endosomal traffic to the lysosome by small GTPases such as Rab4A. In turn, mTORC1 promotes inflammation by skewing T-cell development. Oxidative stress is promoted by mitochondrial electron transport and balanced by the production of reduced glutathione (GSH) and its regeneration by NADPH via the pentose phosphate pathway (PPP). Oxidative stress and activation of mTORC1 inhibit the expression of FoxP3, leading to contraction of the T regulatory (TREG) cell population, and expansion of proinflammatory T-cell lineages such as T helper (TH) 1, TH17, T follicular helper (TFH) and double-negative (DN) T cells. Pharmacological interventions by rapamycin (RAPA), N-acetylcysteine (NAC) and 3-(3-pyridyl)-2-hydroxy-2-phosphonopropanoic acid (3-PEHPC) are highlighted in yellow. AKT, RAC serine/threonine-protein kinase; ANA, antinuclear antibodies; GTP-binding protein Rheb; IFNγ, interferon γ; Lck, tyrosine-protein kinase Lck; PI3K, phosphatidylinositide 3-kinase; Rheb, SLE, systemic lupus erythematosus; TAL, transaldolase; TCR, T-cell receptor; TGFβ1, transforming growth factor β1.

Figure 3. Cell type-specific mTOR pathway activation in rheumatic diseases

The mechanistic target of rapamycin (mTOR) pathway is functional in several types of immune cells, including T cells, B cells and macrophages, but is also present in structural cells such as fibroblasts and keratinocytes. Activation of mTOR in these cells is associated with several rheumatic diseases. AS, ankylosing spondylitis; B_REG, B regulatory cell; DN, CD4/CD8-double-negative cell; CHC, chondrocyte; FLS, fibroblast-like synoviocyte; GN/IN, glomerulonephritis/interstitial nephritis; ILD, interstitial lung disease; Met, metformin; NAC, N-acetylcysteine; OA, osteoarthritis; PB, plasmablast; PC, plasma cell; PHTN, pulmonary hypertension; PsA, psoriatic arthritis; SSc, systemic sclerosis; RA, rheumatoid arthritis, RAPA, rapamycin; SLE, systemic lupus erythematosus; T_FH, T folicular helper cell; T_H1, T helper cell type 1; T_H17, T helper cell type 17; T_REG, T regulatory cell; VEC, vascular endothelial cell; VSMC, vascular smooth-muscle cell.