Targeting macrophage autophagy for inflammation resolution and tissue repair in inflammatory bowel disease

Inflammatory bowel disease(IBD)is a chronic,non-specific,recurrent inflammatory disease,majorly affecting the gastrointestinal tract.Due to its unclear pathogenesis,the current therapeutic strategy for IBD is focused on symptoms alleviation.Autophagy is a lysosome-mediated catabolic process for maintaining cellular homeostasis.Genome-wide association studies and subsequent functional studies have highlighted the critical role of autophagy in IBD via a number of mechanisms,including modulating macrophage function.Macrophages are the gatekeepers of intestinal immune homeostasis,especially involved in regulating inflammation remission and tissue repair.Interestingly,many autophagic proteins and IBD-related genes have been revealed to regulate macrophage function,suggesting that macrophage autophagy is a potentially important process implicated in IBD regulation.Here,we have summarized current understanding of macrophage autophagy function in pathogen and apoptotic cell clearance,inflammation remission and tissue repair regulation in IBD,and discuss how this knowledge can be used as a strategy for IBD treatment.

Corynoxine B targets at HMGB1/2 to enhance autophagy forα-synuclein clearance in fly and rodent models of Parkinson's disease

Parkinson's disease(PD)is the most common neurodegenerative movement disease.It is featured by abnormal alphα-synuclein(α-syn)aggregation in dopaminergic neurons in the substantia nigra.Macroautophagy(autophagy)is an evolutionarily conserved cellular process for degradation of cellular contents,including protein aggregates,to maintain cellular homeostasis.Corynoxine B(Cory B),a natural alkaloid isolated from Uncaria rhynchophylla(Miq.)Jacks.,has been reported to promote the clearance ofα-syn in cell models by inducing autophagy.However,the molecular mechanism by which Cory B induces autophagy is not known,and theα-syn-lowering activity of Cory B has not been verified in animal models.Here,we report that Cory B enhanced the activity of Beclin 1/VPS34 complex and increased autophagy by promoting the interaction between Beclin 1 and HMGB1/2.Depletion of HMGB1/2 impaired Cory B-induced autophagy.We showed for the first time that,similar to HMGB1,HMGB2 is also required for autophagy and depletion of HMGB2 decreased autophagy levels and phosphatidylinositol 3-kinaseⅢactivity both under basal and stimulated conditions.By applying cellular thermal shift assay,surface plasmon resonance,and molecular docking,we confirmed that Cory B directly binds to HMGB1/2 near the C106 site.Furthermore,in vivo studies with a wild-typeα-syn transgenic drosophila model of PD and an A53Tα-syn transgenic mouse model of PD,Cory B enhanced autophagy,promotedα-syn clearance and improved behavioral abnormalities.Taken together,the results of this study reveal that Cory B enhances phosphatidylinositol 3-kinaseⅢactivity/autophagy by binding to HMGB1/2 and that this enhancement is neuroprotective against PD.