Thymosin β4 promotes autophagy and repair via HIF-1α stabilization in chronic granulomatous disease
| Autor: | Luigina Romani, Andrea Finocchi, Giorgia Renga, Allan L. Goldstein, Stefano Brancorsini, Andrea Bartoli, Paolo Rossi, Paolo Mosci, Claudia Stincardini, Silvia Moretti, Vasilis Oikonomou, Claudio Costantini, Marilena Pariano, Enrico Garaci, Marina M. Bellet |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male DNA Repair Health Toxicology and Mutagenesis Inflammation Plant Science Granulomatous Disease Chronic Biochemistry Genetics and Molecular Biology (miscellaneous) 03 medical and health sciences Mice 0302 clinical medicine Chronic granulomatous disease Fibrosis medicine Autophagy Animals Humans Colitis Research Articles NADPH oxidase Ecology biology business.industry NADPH Oxidases Inflammasome medicine.disease Hypoxia-Inducible Factor 1 alpha Subunit Settore MED/38 Actins 3. Good health Mice Inbred C57BL Thymosin 030104 developmental biology RAW 264.7 Cells 030220 oncology & carcinogenesis biology.protein Cancer research Female medicine.symptom Wound healing business hormones hormone substitutes and hormone antagonists medicine.drug Research Article |
| Zdroj: | Life Science Alliance |
| ISSN: | 2575-1077 |
| Popis: | This study demonstrates that thymosin β4 stabilizes HIF-1a to promote autophagy and up-regulate genes involved in tissue and mucosal barrier protection in chronic granulomatous disease. Chronic granulomatous disease (CGD) is a genetic disorder of the NADPH oxidase characterized by increased susceptibility to infections and hyperinflammation associated with defective autophagy and increased inflammasome activation. Herein, we demonstrate that thymosin β4 (Tβ4), a g-actin sequestering peptide with multiple and diverse intracellular and extracellular activities affecting inflammation, wound healing, fibrosis, and tissue regeneration, promoted in human and murine cells noncanonical autophagy, a form of autophagy associated with phagocytosis and limited inflammation via the death-associated protein kinase 1. We further show that the hypoxia inducible factor-1 (HIF-1)α was underexpressed in CGD but normalized by Tβ4 to promote autophagy and up-regulate genes involved in mucosal barrier protection. Accordingly, inflammation and granuloma formation were impaired and survival increased in CGD mice with colitis or aspergillosis upon Tβ4 treatment or HIF-1α stabilization. Thus, the promotion of endogenous pathways of inflammation resolution through HIF-1α stabilization is druggable in CGD by Tβ4. |
| Databáze: | OpenAIRE |
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