Comparative Transcriptional and Phenotypic Peripheral Blood Analysis of Kidney Recipients Under Cyclosporin A or Sirolimus Monotherapy

Brouard, Sophie; Puig-Pey, I.; Lozano, Juan José; Pallier, Annaïck; Braud, Christophe; Giral, Magali; Guillet, Marina; Londoño, M-C; Oppenheimer, F.; Campistol, Josep M.; Soulillou, Jean‐Paul; Sánchez‐Fueyo, Alberto

doi:10.1111/j.1600-6143.2010.03302.x

Cited by 48 publications

(48 citation statements)

References 52 publications

(62 reference statements)

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“…The present study by Brouard et al (2) adds strong in vivo evidence to the persuasive proinflammatory properties of mTOR inhibitors mediated via the innate immune system. At present, our understanding of mTOR inhibitors as mere immunosuppressive agents expands to a more complex and exciting view of highly specific immunoregulators influencing allogeneic, regulatory, memory and inflammatory responses.…”

Section: Weichhart and Säemannsupporting

confidence: 57%

Sirolimus and Kidney Transplantation: Unraveling an Inflammatory Affair

Weichhart

Säemann

2010

American Journal of Transplantation

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Section: Weichhart and Säemannsupporting

confidence: 57%

Sirolimus and Kidney Transplantation: Unraveling an Inflammatory Affair

Weichhart

Säemann

2010

American Journal of Transplantation

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“…Rapa significantly blocked the anti-inflammatory effects of glucocorticoids in myeloid immune cells including monocytes and DCs 29 . Rapa treatment enriched NF-kB-related proinflammatory expression pathways and monocyte lineagespecific transcripts in kidney-transplanted recipients 30 . TSC2 À / À mouse embryonic fibroblasts and TSC2-knockdown THP1 cells both expressed less IL-12 and TNF-a but more IL-10 (ref.…”

Section: Discussionmentioning

confidence: 99%

TSC1 controls macrophage polarization to prevent inflammatory disease

et al. 2014

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Macrophages acquire distinct phenotypes during tissue stress and inflammatory responses, but the mechanisms that regulate the macrophage polarization are poorly defined. Here we show that tuberous sclerosis complex 1 (TSC1) is a critical regulator of M1 and M2 phenotypes of macrophages. Mice with myeloid-specific deletion of TSC1 exhibit enhanced M1 response and spontaneously develop M1-related inflammatory disorders. However, TSC1-deficient mice are highly resistant to M2-polarized allergic asthma. Inhibition of the mammalian target of rapamycin (mTOR) fails to reverse the hypersensitive M1 response of TSC1-deficient macrophages, but efficiently rescues the defective M2 polarization. Deletion of mTOR also fails to reverse the enhanced inflammatory response of TSC1-deficient macrophages. Molecular studies indicate that TSC1 inhibits M1 polarization by suppressing the Ras GTPase-Raf1-MEK-ERK pathway in mTOR-independent manner, whereas TSC1 promotes M2 properties by mTOR-dependent CCAAT/enhancer-binding protein-b pathways. Overall, these findings define a key role for TSC1 in orchestrating macrophage polarization via mTOR-dependent and independent pathways.

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“…35,36 Moreover, kidney transplant patients on rapamycin display enhanced expression of NF-B-related proinflammatory expression pathways and monocyte enrichment compared with CsA patients after being on steroid therapy. 37 In the present study, we determined the role of mTOR in monocytes and myeloid DCs in the context of other currently used immunosuppressive drugs. Our data demonstrate a conspicuous repressive role of mTOR in innate immune cells that interferes with the potent anti-inflammatory effects of GCs.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of mTOR blocks the anti-inflammatory effects of glucocorticoids in myeloid immune cells

Weichhart

Haidinger

Karl

et al. 2011

Blood

120

107

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A central role for the mammalian target of rapamycin (mTOR) in innate immunity has been recently defined by its ability to limit proinflammatory mediators. Although glucocorticoids (GCs) exert potent anti-inflammatory effects in innate immune cells, it is currently unknown whether the mTOR pathway interferes with GC signaling. Here we show that inhibition of mTOR with rapamycin or Torin1 prevented the anti-inflammatory potency of GC both in human monocytes and myeloid dendritic cells. GCs could not suppress nuclear factor-B and JNK activation, the expression of proinflammatory cytokines, and the promotion of Th1 responses when mTOR was inhibited. Interestingly, long-term activation of monocytes with lipopolysaccharide enhanced the expression of TSC2, the principle negative regulator of mTOR, whereas dexamethasone blocked TSC2 expression and reestablished mTOR activation. IntroductionCurrent immunosuppressive regimens to avoid allogeneic rejection after organ or bone marrow transplantation largely rely on drugs with potent immunosuppressive effects predominantly affecting different steps during T-cell activation. There is, however, increasing evidence that also the innate immune system is critical for the fate of allografts and may as well exert detrimental effector functions. 1-9 For example, monocytes are the first cells to enter the allograft immediately after transplantation; and recently, monocyte influx, rather than T-cell influx, into the allograft has been proposed to correlate with graft rejection. 9 Monocytes, macrophages, and dendritic cells (DCs) initiate the inflammatory response after stimulation by Toll-like receptor (TLR) ligands and trigger the subsequent adaptive T-cell response. 10,11 However, the molecular pathways targeted by immunosuppressants in particular when they are used as combination therapy and the ensuing functional consequences are still incompletely defined.Among the currently used immunosuppressants calcineurin inhibitors (CNI), such as cyclosporine A (CsA) or FK506, and antimetabolites, such as mycophenolic acid (mycophenolate mofetil [MMF]) are thought to exert distinct but rather modest effects on innate immune cells. 12,13 On the contrary, glucocorticoids (GCs) have a high anti-inflammatory potential and, consequently, are crucial constituents of various immunosuppressive regimens applied in many inflammatory conditions. 14 GCs differentially affect cytokine production in monocytes/macrophages with a prominent shift toward an anti-inflammatory phenotype. 15 Furthermore, DC differentiation and maturation are profoundly suppressed by GCs, leading to DCs with a tolerizing capacity characterized by increased interleukin-10 (IL-10), but blocked IL-12 secretion. 16,17 At the molecular level, GCs profoundly inhibit nuclear factor-B (NF-B) signaling via the glucocorticoid receptor (GR) to prevent recruitment of active NF-B dimers to the B promoter. 18 Moreover, it has been demonstrated that the c-Jun N-terminal kinase (JNK) pathway that specifically leads to the activation of the tr...

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Comparative Transcriptional and Phenotypic Peripheral Blood Analysis of Kidney Recipients Under Cyclosporin A or Sirolimus Monotherapy

Cited by 48 publications

References 52 publications

Sirolimus and Kidney Transplantation: Unraveling an Inflammatory Affair

Sirolimus and Kidney Transplantation: Unraveling an Inflammatory Affair

TSC1 controls macrophage polarization to prevent inflammatory disease

Inhibition of mTOR blocks the anti-inflammatory effects of glucocorticoids in myeloid immune cells

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