High expression of mTOR signaling in granulomatous lesions is not predictive for the clinical course of sarcoidosis

Pizzini, Alex; Bacher, Hannes; Aichner, Magdalena; Franchi, Alexander; Watzinger, K; Tancevski, Ivan; Sonnweber, Thomas; Mosheimer-Feistritzer, Birgit; Duftner, Christina; Zelger, Bettina; Pallua, Johannes; Sprung, Susanne; Weichhart, Thomas; Zelger, Bernhard; Weiß, Günter; Löffler‐Ragg, Judith

doi:10.1016/j.rmed.2020.106294

Cited by 13 publications

(6 citation statements)

References 33 publications

(37 reference statements)

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“…Whether mTORC1 activity directly induces the expression of E-cadherin or other genes involved in the epithelioid transformation of macrophages remains unknown. However, mutations in mTOR-related genes have been detected in familial sarcoidosis ( 38 ), and phagosome-regulated mTORC1 signaling is required for granuloma formation in vitro ( 39 ), even if the exacerbated signaling in granulomatous lesions failed to predict disease course ( 40 ). Our results position PTX3 as a critical upstream regulator that inhibits the detrimental activation of mTORC1 and the associated granuloma-promoting cues in macrophages.…”

Section: Discussionmentioning

confidence: 99%

Pentraxin 3 Inhibits Complement-driven Macrophage Activation to Restrain Granuloma Formation in Sarcoidosis

Gonçales

Bastos

Duarte-Oliveira

et al. 2022

Am J Respir Crit Care Med

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Rationale Sarcoidosis is a multisystemic inflammatory disease characterized by the formation of granulomas in response to persistent stimuli. The long pentraxin PTX3 (pentraxin 3) has emerged as a component of humoral innate immunity with essential functions in the resolution of inflammation, but its role during granuloma formation is unknown. Objectives To evaluate PTX3 as a modulator of pathogenic signals involved in granuloma formation and inflammation in sarcoidosis. Methods Peripheral blood mononuclear cells obtained from patients with sarcoidosis harboring loss-of-function genetic variants and gene-deleted mice were used to assess the role of PTX3 in experimental models of granuloma formation in vitro and in vivo . The identified mechanisms of granulomatous inflammation were further evaluated in tissue and BAL samples and correlated with the disease course. Measurements and Main Results We have identified a molecular link between PTX3 deficiency and the pathogenic amplification of complement activation to promote granuloma formation. Mechanistically, PTX3 deficiency licensed the complement component C5a-mediated activation of the metabolic checkpoint kinase mTORC1 (mammalian target of rapamycin complex 1) and the reprogramming of macrophages toward increased glycolysis to foster their proliferation and aggregation. This process sustained the further recruitment of granuloma-promoting immune cells and the associated proinflammatory microenvironment and influenced the clinical course of the disease. Conclusions Our results identify PTX3 as a pivotal molecule that regulates complement-mediated signaling cues in macrophages to restrain granulomatous inflammation and highlight the therapeutic potential of this signaling axis in targeting granuloma formation in sarcoidosis.

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Section: Discussionmentioning

confidence: 99%

Pentraxin 3 Inhibits Complement-driven Macrophage Activation to Restrain Granuloma Formation in Sarcoidosis

Gonçales

Bastos

Duarte-Oliveira

et al. 2022

Am J Respir Crit Care Med

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“…Recently, Pizzini et al studied mTORC1 activation in a cohort of 58 patients with sarcoidosis, and demonstrated that all patients had a positive activation of S6K [ 11 ], which is not in concordance with the 33% of patients described by Linke et al…”

Section: Introductionmentioning

confidence: 96%

Activation of Downstream mTORC1 Target Ribosomal Protein S6 Kinase (S6K) Can Be Found in a Subgroup of Dutch Patients with Granulomatous Pulmonary Disease

Kraaijvanger

Seldenrijk

Beijer

et al. 2021

Cells

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Mechanistic target of rapamycin complex 1 (mTORC1) has been linked to different diseases. The mTORC1 signaling pathway is suggested to play a role in the granuloma formation of sarcoidosis. Recent studies demonstrated conflicting data on mTORC1 activation in patients with sarcoidosis by measuring activation of its downstream target S6 kinase (S6K) with either 33% or 100% of patients. Therefore, the aim of our study was to reevaluate the percentage of S6K activation in sarcoidosis patients in a Dutch cohort. To investigate whether this activation is specific for sarcoid granulomas, we also included Dutch patients with other granulomatous diseases of the lung. The activation of the S6K signaling pathway was evaluated by immunohistochemical staining of its downstream effector phospho-S6 in tissue sections. Active S6K signaling was detected in 32 (43%) of the sarcoidosis patients. Twelve (31%) of the patients with another granulomatous disorder also showed activated S6K signaling, demonstrating that the mTORC1 pathway may be activated in a range for different granulomatous diseases (p = 0.628). Activation of S6K can only be found in a subgroup of patients with sarcoidosis, as well as in patients with other granulomatous pulmonary diseases, such as hypersensitivity pneumonitis or vasculitis. No association between different clinical phenotypes and S6K activation can be found in sarcoidosis.

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“…In addition, mTORC1 regulates protein synthesis by phosphorylating S6K1 and 4EBP1 [40] . Therefore, phosphorylated S6K1 and phosphorylated 4EBP1 can be regarded as markers of activated mTOR signaling [41][42] . The PI3K/AKT/mTOR signal transduction pathway is crucial in immune cells [43] , as through its action on activated downstream effector molecules, it can inhibit cell apoptosis and promote cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

Campanumoea javanica Bl. activates the PI3K/AKT/mTOR signaling pathway and reduces sarcopenia in a T2DM rat model

Zuo

Yao

Zhao

et al. 2022

Acupuncture and Herbal Medicine

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Objective: Sarcopenia causes loss of skeletal muscle and function, thus seriously affecting the physical function and quality of life in the elderly. This article discusses the specific molecular mechanism and ameliorating effects of Tudangshen (TDS) on sarcopenia in elderly rats with type 2 diabetes mellitus (T2DM).Methods: Elderly Sprague-Dawley (SD) rats were randomly selected and fed with a high-fat diet combined with an intraperitoneal injection of streptozotocin to establish T2DM model. The model rats were stratified and randomly divided into the model group, metformin group, TDS high-dose group, TDS medium-dose group, and TDS low-dose group according to blood glucose combined with body weight, and the same batch of old SD rats was set as the normal control group. The effects of TDS in an elderly T2DM sarcopenia rat model were evaluated by observing the body positions of the rats, analyzing blood biochemistry, testing exercise capacity, and pathologically staining sectioned gastrocnemius muscle tissues. The molecular mechanisms of the effects were analyzed using quantitative real-time polymerase chain reaction and western blotting.Results: TDS has no statistically significant effect on blood glucose, insulin and glycosylated serum protein in aged rats with T2DM, but it can reduce levels of glycosylated serum protein, total cholesterol, triglycerides, and low-density lipoprotein; it improves pathological changes in rat gastrocnemius muscle tissues, and increases muscle cell activity in elderly rats with T2DM and sarcopenia. TDS also promoted the upregulation of the expression of mammalian target of rapamycin (mTOR)/protein kinase B (PKB/AKT)/phosphatidylinositol 3-kinase (PI3K)/ribosomal protein S6 kinase/eukaryotic initiation factor 4E binding rotein1 mRNA in rats and triggered an increase in corresponding protein levels.Conclusions: TDS alleviated muscle decline in elderly rats with T2DM by activating the PI3K/AKT/mTOR signaling pathway and regulating the synthesis of corresponding proteins.

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High expression of mTOR signaling in granulomatous lesions is not predictive for the clinical course of sarcoidosis

Cited by 13 publications

References 33 publications

Pentraxin 3 Inhibits Complement-driven Macrophage Activation to Restrain Granuloma Formation in Sarcoidosis

Pentraxin 3 Inhibits Complement-driven Macrophage Activation to Restrain Granuloma Formation in Sarcoidosis

Activation of Downstream mTORC1 Target Ribosomal Protein S6 Kinase (S6K) Can Be Found in a Subgroup of Dutch Patients with Granulomatous Pulmonary Disease

Campanumoea javanica Bl. activates the PI3K/AKT/mTOR signaling pathway and reduces sarcopenia in a T2DM rat model

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