Abstract
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.
Highlights
Chronic granulomatous disease (CGD) is an immunodeficiency caused by mutations in the proteins forming the NADPH complex, which results in defective production of reactive oxygen species (ROS), impaired microbial killing by phagocytic cells, and increased susceptibility to infections (Rider et al, 2018)
In order to assess the ability of thymosin β4 (Tβ4) to promote autophagy, we first evaluated the ratio of LC3-II to LC3-I, widely used to monitor autophagy (Oikonomou et al, 2016), on RAW264.7 cells exposed to live Aspergillus conidia in the presence of different concentrations of Tβ4
The expression of death-associated protein kinase 1 (DAPK1) and Rubicon proteins, known to be involved in LC3-associated phagocytosis (LAP) (Martinez et al, 2016), was dose-dependently increased by Tβ4 (Fig 1C), a finding suggesting that Tβ4 promotes noncanonical autophagy involving DAPK1 and Rubicon
Summary
Chronic granulomatous disease (CGD) is an immunodeficiency caused by mutations in the proteins forming the NADPH complex, which results in defective production of reactive oxygen species (ROS), impaired microbial killing by phagocytic cells, and increased susceptibility to infections (Rider et al, 2018). Different from canonical autophagy, LAP is activated during phagocytosis upon recognition of microbes by pattern recognition receptors for rapid pathogen degradation (Simon & Clarke, 2016; Sprenkeler et al, 2016). A mechanism by which inflammation is regulated during LAP has been recently described and involves the death-associated protein kinase 1 (DAPK1) (Oikonomou et al, 2016), a kinase mediating many different cellular functions such as cell death and repair (Bialik & Kimchi, 2006; Singh et al, 2016). Activated by IFN-γ, DAPK1 mediates LAP of the fungus Aspergillus fumigatus and concomitantly inhibits nod-like receptor protein 3 (NLRP3) activation, restraining pathogenic inflammation (Oikonomou et al, 2016). DAPK1 activity was defective in murine and human CGD (Oikonomou et al, 2016), a finding suggesting that the LAP/DAPK1 axis may represent a druggable pathway in CGD (Oikonomou et al, 2018)
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