Loss of asparagine endopeptidase impairs autophagic degradation and enhances endotoxin-induced TNF-α production in M2 macrophages (INM8P.358)

Abstract Asparagine endopeptidase (AEP) has been shown to play important roles in innate immunity. Here, we show that AEP is a previously unrecognized regulator of autophagy in M2 macrophages. AEP interacted with PI3K p110α and suppressed PI3K activation on the endomembranes. AEP deficiency led to abnormal activation of PI3K, which converted phosphatidyinositol (4,5)-bisphosphate (PIP2) to phosphatidyinositol (3,4,5)-bisphosphate (PIP3) (PIP3). Decrease in PIP2 and increase in PIP3 resulted in impaired autophagic lysosome biogenesis and autolysosome clearance. Impaired autolysosome clearance in turn led to accumulation of NF-κB proteins, which promoted proinflammatory cytokine synthesis upon LPS stimulation. Moreover, AEP-/- mice showed significantly enhanced inflammation when stimulated with LPS or challenged with S. Japonicum eggs. Induction of autophagy with raramycin in AEP-/- mice and inhibition of autophagy with Bafilomaycin A1 in WT mice prevented and increased S. Japonicum eggs induced granulomas respectively. Thus, our data linked AEP to the immunosuppressive phenotype of M2 macrophages through promoting autophagy.