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

Abstract

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.

Simultaneous Assessment of mTORC1, JAK/STAT, and NLRP3 Inflammasome Activation Pathways in Patients with Sarcoidosis

“…In addition, they identified activation of this pathway in one third of granulomas obtained from 27 biopsies from sarcoidosis patients. Data from our own group confirmed these findings with the activation of the mTORC1 pathway seen in 43% of 74 Dutch sarcoidosis patients [7]. Furthermore, Linke et al [6] reported that by treating mice with everolimus, an mTOR inhibitor, the granuloma in the mice completely resolved.…”

“…Immunohistochemical staining procedure, as well as the used antibody for mTORC1 staining, was previously described in [ 7 ]. In order to study the role of the JAK/STAT signaling pathway in granuloma formation and pathogenesis of sarcoidosis, we performed immunohistochemical staining of the activated form of STAT1 and STAT3, phosphorylated STAT1 (p-STAT1) and p-STAT3 (Cell Signaling Technology, Inc., Danvers, MA, USA).…”