Thymosin β4 promotes autophagy and repair via HIF-1α stabilization 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 beta 4 (T beta 4), 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)alpha was underexpressed in CGD but normalized by T beta 4 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 T beta 4 treatment or HIF-1 alpha stabilization. Thus, the promotion of endogenous pathways of inflammation resolution through HIF-1 alpha stabilization is druggable in CGD by T beta 4.