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 Renga, Giorgia
A1 Oikonomou, Vasilis
A1 Moretti, Silvia
A1 Stincardini, Claudia
A1 Bellet, Marina M
A1 Pariano, Marilena
A1 Bartoli, Andrea
A1 Brancorsini, Stefano
A1 Mosci, Paolo
A1 Finocchi, Andrea
A1 Rossi, Paolo
A1 Costantini, Claudio
A1 Garaci, Enrico
A1 Goldstein, Allan L
A1 Romani, Luigina
YR 2019
UL http://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.