Thymosin β4 promotes autophagy and repair via HIF-1α stabilization in chronic granulomatous disease

Medientyp: E-Artikel

Titel: Thymosin β4 promotes autophagy and repair via HIF-1α stabilization in chronic granulomatous disease

Beteiligte: Renga, Giorgia; Oikonomou, Vasilis; Moretti, Silvia; Stincardini, Claudia; Bellet, Marina M; Pariano, Marilena; Bartoli, Andrea; Brancorsini, Stefano; Mosci, Paolo; Finocchi, Andrea; Rossi, Paolo; Costantini, Claudio; Garaci, Enrico; Goldstein, Allan L; Romani, Luigina

Erschienen: Life Science Alliance, LLC, 2019

Sprache: Englisch

DOI: 10.26508/lsa.201900432

ISSN: 2575-1077

Schlagwörter: Health, Toxicology and Mutagenesis ; Plant Science ; Biochemistry, Genetics and Molecular Biology (miscellaneous) ; Ecology

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Beschreibung: 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.

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