Reconstruction of the Cytokine Signaling in Lysosomal Storage Diseases by Literature Mining and Network Analysis.

Lysosomal storage diseases (LSDs) are characterized by the abnormal accumulation of substrates in tissues due to the deficiency of lysosomal proteins. Among the numerous clinical manifestations, chronic inflammation has been consistently reported for several LSDs. However, the molecular mechanisms involved in the inflammatory response are still not completely understood. In this study, we performed text-mining and systems biology analyses to investigate the inflammatory signals in three LSDs characterized by sphingolipid accumulation: Gaucher disease, Acid Sphingomyelinase Deficiency (ASMD), and Fabry Disease. We first identified the cytokines linked to the LSDs, and then built on the extracted knowledge to investigate the inflammatory signals. We found numerous transcription factors that are putative regulators of cytokine expression in a cell-specific context, such as the signaling axes controlled by STAT2, JUN, and NR4A2 as candidate regulators of the monocyte Gaucher disease cytokine network. Overall, our results suggest the presence of a complex inflammatory signaling in LSDs involving many cellular and molecular players that could be further investigated as putative targets of anti-inflammatory therapies.

Informations de copyright

Copyright © 2021 Parolo, Tomasoni, Bora, Ramponi, Kaddi, Azer, Domenici, Neves-Zaph and Lombardo.

Déclaration de conflit d'intérêts

CK and SN-Z are current employees of Sanofi and may hold shares and/or stock options in the company. KA was employee of Sanofi while the initial phase of this study was conducted. SP, RL, DT, PB, and ED were contracted by Sanofi while the initial phase of this study was conducted. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.