Dysfunctional autophagy following exposure to pro-inflammatory cytokines contributes to pancreatic β-cell apoptosis

摘要: Type 1 diabetes (T1D) results from β-cell destruction due to concerted action of both innate and adaptive immune responses. Pro-inflammatory cytokines, such as interleukin-1β interferon-γ, secreted by the cells invading islets Langerhans, contribute pancreatic death in T1D. Cytokine-induced endoplasmic reticulum (ER) stress plays a central role demise. ER can modulate autophagic response; however, no study addressed regulation autophagy during pathophysiology In this study, we document that cytokines activate AMPK-ULK-1 pathway while inhibiting mTORC1, which stimulates activity an stress-dependent manner. On other hand, time-course analysis LC3-II accumulation autophagosomes revealed block flux independent manner, leading formation large dysfunctional worsening stress. Cytokines rapidly impair lysosome function, membrane permeabilization, Cathepsin B leakage lysosomal cell death. Blocking cathepsin partially protects against cytokine-induced or torin1-induced apoptosis, whereas blocking aggravates CHOP overexpression apoptosis. conclusion, stimulate early steps flux, aggravate trigger Restoration autophagy/lysosomal function may represent novel strategy improve resistance context