1. TFEB signaling attenuates NLRP3-driven inflammatory responses in severe asthma
- Author
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Efthymia Theofani, Maria Semitekolou, Konstantinos Samitas, Annie Mais, Ioanna E. Galani, Vasiliki Triantafyllia, Joanna Lama, Ioannis Morianos, Athanasios Stavropoulos, Se‐Jin Jeong, Evangelos Andreakos, Babak Razani, Nikoletta Rovina, and Georgina Xanthou
- Subjects
Mice ,Basic Helix-Loop-Helix Leucine Zipper Transcription Factors ,Inflammasomes ,Immunology ,NLR Family, Pyrin Domain-Containing 3 Protein ,Autophagy ,Immunology and Allergy ,Animals ,Mechanistic Target of Rapamycin Complex 1 ,Reactive Oxygen Species ,Asthma - Abstract
NLRP3-driven inflammatory responses by circulating and lung-resident monocytes are critical drivers of asthma pathogenesis. Autophagy restrains NLRP3-induced monocyte activation in asthma models. Yet, the effects of autophagy and its master regulator, transcription factor EB (TFEB), on monocyte responses in human asthma remain unexplored. Here, we investigated whether activation of autophagy and TFEB signaling suppress inflammatory monocyte responses in asthmatic individuals.Peripheral blood CD14We observed increased NLRP3 inflammasome activation, concomitant with impaired autophagy in circulating monocytes that correlated with asthma severity. SA patients also exhibited mitochondrial dysfunction and ROS accumulation. Autophagy failed to inhibit NLRP3-driven monocyte responses, due to defective TFEB activation and excessive mTORC1 signaling. NLRP3 blockade restrained inflammatory cytokine release and linked airway disease. TFEB activation restored impaired autophagy, attenuated NLRP3-driven pulmonary inflammation, and ameliorated SA phenotype.Our studies uncover a crucial role for TFEB-mediated reprogramming of monocyte inflammatory responses, raising the prospect that this pathway can be therapeutically harnessed for the management of SA.
- Published
- 2021