Abstract
IntroductionSarcoidosis is a systemic granulomatous disease with a variable clinical presentation and disease course. There is still no reliable biomarker available, which assists in the diagnosis or prediction of the clinical course. According to a murine model, the expression level of the metabolic checkpoint kinase mechanistic target of Rapamycin complex 1 (mTORC1) in granulomas of sarcoidosis patients may be used as a clinical biomarker. Material and methodsThis is a retrospective analysis of 58 patients with histologically confirmed sarcoidosis. Immunohistochemical staining of granulomas from tissue samples was evaluated for the expression of activated mTORC1 signaling, including phosphorylated mTOR, its downstream effectors S6K1, 4EBP1 and the proliferation marker Ki-67. Patients were categorized according to different clinical phenotypes, serum biomarkers, and immunomodulatory therapy. ResultsAll patients showed activated mTORC1 signaling in granulomas, which correlated with its downstream effectors S6K1 and 4EBP1 but was not related to Ki-67 expression. The mTORC1 activity revealed an association neither to disease severity nor the necessity of treatment; however, p-mTOR inversely correlated with cumulative corticosteroid dosage. ConclusionOur data confirm activation of the mTORC1 pathway in sarcoidosis, supporting the hypothesis that mTOR is a significant driver in granuloma formation. However, we could not find a relationship between the degree of mTOR activation and disease severity or the need for therapy.
Highlights
Sarcoidosis is a systemic granulomatous disease with a variable clinical presentation and disease course
The serine/threonine protein kinase mTOR, standing for mechanistic target of rapamycin [8] forms the catalytic subunit of two protein complexes called mTOR complex 1 and mTOR complex 2 and plays a pivotal role in cell physi ology regulating the function and metabolism of innate and adaptive immune cell populations [9,10,11]. mechanistic target of Rapamycin complex 1 (mTORC1) further consists of the regu latory protein associated with mTOR (Raptor) and the mammalian lethal with Sec13 protein 8 [12,13]
MTORC1 functions as an inhibitor of autophagy as demonstrated by pharmaco logic blockage of mTORC1 resulting in autophagy induction [17]. mTOR is negatively upregulated by tuberous sclerosis protein 2 (TSc2) [18]
Summary
Sarcoidosis is a systemic granulomatous disease with a variable clinical presentation and disease course. According to a murine model, the expression level of the metabolic checkpoint kinase mechanistic target of Rapamycin complex 1 (mTORC1) in granulomas of sarcoidosis patients may be used as a clinical biomarker. Immunohistochemical staining of granulomas from tissue samples was evaluated for the expression of activated mTORC1 signaling, including phosphorylated mTOR, its downstream effectors S6K1, 4EBP1 and the proliferation marker Ki-67. Results: All patients showed activated mTORC1 signaling in granulomas, which correlated with its downstream effectors S6K1 and 4EBP1 but was not related to Ki-67 expression. The mTORC1 activity revealed an association neither to disease severity nor the necessity of treatment; p-mTOR inversely correlated with cumulative corticosteroid dosage. Conclusion: Our data confirm activation of the mTORC1 pathway in sarcoidosis, supporting the hypothesis that mTOR is a significant driver in granuloma formation. MTORC1 functions as an inhibitor of autophagy as demonstrated by pharmaco logic blockage of mTORC1 resulting in autophagy induction [17]. mTOR is negatively upregulated by tuberous sclerosis protein 2 (TSc2) [18]
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