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

Abstract

The unknown etiology of sarcoidosis, along with the variability in organ involvement and disease course, complicates the effective treatment of this disease. Based on recent studies, the cellular inflammatory pathways involved in granuloma formation are of interest regarding possible new treatment options, such as the mechanistic (formerly mammalian) target of rapamycin complex 1 (mTORC1) pathway, the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway, and the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome pathway. The aim of this study was to explore the potential coexpression of these three inflammatory pathways in patients with sarcoidosis and see whether possible differences were related to disease outcome. The tissue of 60 patients with sarcoidosis was used to determine the activity of these three signaling pathways using immunohistochemistry. The activation of NLRP3 was present in 85% of all patients, and the activation of mTORC1 and JAK/STAT was present in 49% and 50% of patients, respectively. Furthermore, the presence of NLRP3 activation at diagnosis was associated with a chronic disease course of sarcoidosis. Our finding of different new conceptual inflammatory tissue phenotypes in sarcoidosis could possibly guide future treatment studies using the available inhibitors of either NLRP3, JAK-STAT, and mTORC1 inhibitors in a more personalized medicine approach.

Cumulative incidence and risk of infection in patients with rheumatoid arthritis treated with janus kinase inhibitors: A systematic review and meta-analysis

“…In our analysis, patients receiving the JAKi baricitinib were significantly more likely to develop opportunistic infections compared to patients in the control group. The increased risk of opportunistic infections in patients receiving JAKi has been attributed to down-modulation of cytokines responsible for mounting T-cell specific responses against pathogens [ 64 ], impaired granuloma formation necessary for containment of infections, such as tuberculosis [ 65 ], and diminished interferon-mediated antiviral responses that protect against viral infections [ 66 ]. The most common infections as a result of JAKi therapy reported in our analysis and other published studies, in addition to herpes zoster, include Candida spp., followed by infections from cytomegalovirus, Cryptococcus spp., Pneumocystis jirovecii , and tuberculosis [ 57 , 67 ].…”