Akt-Dependent Enhanced Migratory Capacity of Th17 Cells from Children with Lupus Nephritis

Kshirsagar, Sudhir; Riedl, Magdalena; Billing, Heiko; Tönshoff, Burkhard; Thangavadivel, Shanmugapriya; Steuber, Christian; Staude, Hagen; Wechselberger, Gottfried; Edelbauer, Monika

doi:10.4049/jimmunol.1400044

Cited by 33 publications

(22 citation statements)

References 54 publications

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“…Similarly, studies examining a T cell‐specific mTORC1 deletion found impaired Th17 and Th1 differentiation but increased iTreg differentiation 30 , 31 . Finally, IL‐17‐producing T cells from children with Lupus nephritis show enhanced activation of the AKT/mTOR signaling pathway and an enhanced migratory capacity that could be reduced by inhibition of AKT activity 32 …”

Section: Discussionmentioning

confidence: 92%

Activation of TGF‐β‐induced non‐Smad signaling pathways during Th17 differentiation

et al. 2015

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Although transforming growth factor-β (TGF-β) has been shown to positively regulate the development of murine T helper type 17 (Th17) cells, which of the intracellular signaling pathways are involved is controversial. We examined Smad-dependent and -independent signaling molecules downstream of the TGF-β receptor (TGFβR) involved in Th17 differentiation of naive murine CD4(+)CD62L(+) T cells. During Th17 differentiation of wild-type T cells, Smad2/3 was phosphorylated, indicating activation of the canonical Smad pathway. T cells lacking TGFβRII did not differentiate into Th17, whereas T cells treated with a TGFβRI kinase inhibitor (SB-431542) or overexpression of inhibitory Smad7 retained a low amount of Th17 polarization despite absent Smad2/3 phosphorylation. Using protein antibody arrays we found an increase of expression and phosphorylation of the following Smad-independent signaling molecules in Th17-polarized wild-type T cells: AKT1(Tyr474), AKT2 (Ser474), ERK1-p44/42 MAPK(Tyr204), mTOR(Thr2446), p38 MAPK(Thr180), Rac1/cdc42(Ser71), SAPK/JNK(Tyr185) and SP1(Thr739). Pharmacological inhibition of AKT/mammalian target of rapamycin (mTOR) signaling with rapamycin or LY294002 decreased Th17 differentiation of wild-type T cells, and completely abolished interleukin-17 production in T cells with overexpression of Smad7. Rapamycin and LY294002 also decreased induced regulatory T cell differentiation, but only had minor additive effects to Smad7 overexpression. Finally, inhibitors of mitogen-activated protein kinase (MAPK) blocked in vitro polarization of Th17 cells. Our data show that Smad-dependent and -independent intracellular pathways contribute to murine Th17 differentiation.

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Section: Discussionmentioning

confidence: 92%

Activation of TGF‐β‐induced non‐Smad signaling pathways during Th17 differentiation

et al. 2015

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“…In addition, CAMKIV has been linked to expression of CCR6, which facilitates recruitment of T H17 cells to the kidney[34]. AKT inhibition reduces in vitro T H17 migration in response to CCL-20 [35], probably as a consequence of altered signaling through ROCK, which is more active in SLE T cells and is involved in CCR6 and CD44 signaling [36]. IL-17 also contributes to the loss of B cell tolerance in an autoimmune mouse [37], adding a new role to DN and T H17 cell function in SLE pathogenesis.…”

Section: Increased Numbers Of T Helper 17 Cells Promote Kidney Diseasmentioning

confidence: 99%

T cells in Systemic Lupus Erythematosus

Suárez‐Fueyo

Bradley

Tsokos

2016

Current Opinion in Immunology

164

127

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Systemic Lupus Erythematosus is an autoimmune disorder caused by a complex combination of genetic, epigenetic and environmental factors. Different polymorphisms and epigenetic modifications lead to altered gene expression and function of several molecules which lead to abnormal T cell responses. Metabolic and functional alterations result in peripheral tolerance failures and biased differentiation of T cells into pro-inflammatory and B cell-helper phenotypes as well as the accumulation of disease-promoting memory T cells. Understanding these T cell alterations and their origins is necessary to develop more accurate patient classification systems and to discover new therapeutic targets.

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“…Patients with lupus nephritis have higher STAT3 activity in effector T cells and higher percentage of IL‐17‐producing cells when compared with those of controls . Moreover, the inhibition of mTORC1 signaling by rapamycin reduces both STAT3 activation in effector T cells and percentage of IL‐17‐producing T cells in lupus patients . In T‐ Rheb −/− mice, in which T cells specifically do not express Rheb, a crucial regulator of mTORC1 signaling , T cells fail to differentiate into Th17 cells, and phosphorylation of STAT3 does not occur in response to IL‐6, IL‐10, or IL‐21 .…”

Section: Stat3 and Stat5 In Mtorc1 Signalingmentioning

confidence: 99%

mTORC1 signaling and IL‐17 expression: Defining pathways and possible therapeutic targets

et al. 2015

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IL-17 mediates immune responses against extracellular pathogens, and it is associated with the development and pathogenesis of various autoimmune diseases. The expression of IL-17 is regulated by various intracellular signaling cascades. Recently, it hasbeen shown that mechanistic target of rapamycin (mTOR) signaling, comprised mainly of mTORC1 signaling, plays a critical role in IL-17 expression. Here, we review the current knowledge regarding mechanisms by which mTORC1 regulates IL-17 expression. mTORC1 positively modulates IL-17 expression through several pathways, i.e. STAT3, -HIF-1α, -S6K1, and -S6K2. Amino acids (AAs) also regulate IL-17 expression by being the energy source for Th17 cells, and by activating mTORC1 signaling. Altogether, the AA-mTORC1-IL-17 axis has broad therapeutic implications for IL-17-associated diseases, such as EAE, allergies, and colitis. Keywords: Amino acid IL-17 mTORC1 STAT HIF-1α IntroductionMechanistic target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine protein kinase that integrates diverse environmental signals (i.e. hormones, growth factors, and amino acids) into appropriate cellular metabolism and responses to maintain cellular homeostasis [1]. mTOR refers to two complexes, the mTOR complex 1 (mTORC1) and the mTOR complex 2 (mTORC2), which differ in composition, substrates metabolized, and cellular functions ( Fig. 1) [2, 3]. mTORC1 is composed of mTOR, raptor (regulatory-associated protein of mTOR) [4, 5], mLST8/GβL (mammalian lethal with Correspondence: Prof. Yulong Yin e-mail: yinyulong@isa.ac.cn Sec 13 protein 8/G-protein β-protein subunit like) [6], PRAS40 (Akt/PKB substrate 40kDa) [7, 8], and deptor (DEP-domaincontaining mTOR interacting protein) [9] (Fig. 1A). Raptor recruits substrates to the mTOR kinase through TOS (TOR signaling) motifs on the substrates [10, 11], and PRAS40 and deptor are suppressors and targets of mTORC1, potentially acting as competitive substrates [9, 12]. Interestingly, mLST8/GβL does not appear to be essential for mTORC1 function based on evidence that: (i) unlike the absence of raptor or mTOR in mice, which results in early embryonic lethality (around embryonic day (e) 5.5 [13, 14], mLST8 null mouse embryos survive until e10.5 [14]; and (ii) mLST8 is not necessary to maintain the raptor-mTOR interaction and the phosphorylation of ribosomal S6 kinase 1 (S6K1) [14]. mTORC1 has numerous downstream effectors, including S6Ks, 4EBPs, IRS-1, ULK1, Lipin1, TFEB, and GRB10 [1,15,16]. Through these substrates, the activation of mTORC1 signalingwww.eji-journal.eu 292Wenkai Ren et al. Eur. J. Immunol. 2016. 46: 291-299 Figure 1. Components, substrates, and cellular functions of mTORC1 and mTORC2. (A) mTORC1 is composed of mTOR, raptor, mLST8/GβL, PRAS40, and deptor. mTORC1 promotes protein, lipid, and nucleotide synthesis, cell growth, and proliferation, and inhibition of autophagy through numerous downstream effectors, including S6Ks, 4EBPs, IRS-1, ULK1, Lipin1, TFEB, and GRB10. (B) mTORC2 is composed of mTOR, rictor, mS...

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Akt-Dependent Enhanced Migratory Capacity of Th17 Cells from Children with Lupus Nephritis

Cited by 33 publications

References 54 publications

Activation of TGF‐β‐induced non‐Smad signaling pathways during Th17 differentiation

Activation of TGF‐β‐induced non‐Smad signaling pathways during Th17 differentiation

T cells in Systemic Lupus Erythematosus

mTORC1 signaling and IL‐17 expression: Defining pathways and possible therapeutic targets

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