RT Journal Article
SR Electronic
T1 Thymosin β4 promotes autophagy and repair via HIF-1α stabilization in chronic granulomatous disease
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e201900432
DO 10.26508/lsa.201900432
VO 2
IS 6
A1 Giorgia Renga
A1 Vasilis Oikonomou
A1 Silvia Moretti
A1 Claudia Stincardini
A1 Marina M Bellet
A1 Marilena Pariano
A1 Andrea Bartoli
A1 Stefano Brancorsini
A1 Paolo Mosci
A1 Andrea Finocchi
A1 Paolo Rossi
A1 Claudio Costantini
A1 Enrico Garaci
A1 Allan L Goldstein
A1 Luigina Romani
YR 2019
UL https://www.life-science-alliance.org/content/2/6/e201900432.abstract
AB 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.