Abstract
Endoplasmic reticulum (ER) stress contributes to the development and progression of many chronic inflammatory diseases, including type 2 diabetes, obesity, atherosclerosis, neurodegenerative diseases, and cancer. ER stress has been reported to induce inflammasome activation and release of mature IL-1β, which contributes to many inflammatory diseases. The molecular mechanisms that activate the inflammasome during ER stress are still poorly understood. Here we report that the kinase receptor-interacting protein 1 (RIP1) plays an important role in ER stress-induced activation of inflammasome. Inhibition of RIP1 kinase activity by Necrostatin-1 or siRNA-mediated RIP1 knockdown significantly reduced ER stress-induced caspase-1 cleavage and IL-1β secretion in both bone marrow-derived macrophages (BMDMs) and J774A.1 macrophages. We speculate that the mitochondria fission factor dynamin-related protein 1 (DRP1) and reactive oxygen species (ROS) might function as the effectors downstream of RIP1 to mediate inflammasome activation. Our study reveals a critical role for RIP1 in regulating ER stress-induced inflammation responses, and proposes RIP1 as a potential pharmaceutical target to treat diseases resulting from unresolved ER stress-related inflammation.
Highlights
The endoplasmic reticulum (ER), which functions as the main cellular endomembrane organelle for protein folding and lipid synthesis, has been suggested to be a sensitive stress sensor in eukaryotic cells
To explore the role of receptor-interacting protein 1 (RIP1) in ER stress-induced inflammasome activation, we treated cells with RIP1 kinase inhibitor Necstatin-1 (Nec-1) and found that Nec-1 pretreatment significantly decreased the IL-1β secretion induced by LPS plus TG, but not affecting the IL-1β release induced by Nigericin in both bone marrowderived macrophages (BMDMs) and J774A.1 macrophages (Fig. 1e–j), which was consistent with our and others’ previous studies that Nec-1 fails to affect Nigericin-induced NLRP3 inflammasome activation[12,14]
The results indicated that Mdivi-1 pretreatment significantly inhibited IL-1β production as well as caspase-1 cleavage induced by ER stress in BMDMs (Fig. 4e–g), supporting the results of dynamin-related protein 1 (DRP1) small interfering RNA (siRNA) which suggested a critical role of DRP1 in ER stress-induced inflammasome activation
Summary
The endoplasmic reticulum (ER), which functions as the main cellular endomembrane organelle for protein folding and lipid synthesis, has been suggested to be a sensitive stress sensor in eukaryotic cells. Nec-1 obviously suppressed the caspase-1 cleavage induced by LPS plus TG (Fig. 1k), suggesting that RIP1 kinase inhibition blocked the ER stress-induced inflammasome activation. Knocking down the expression of RIP1 by siRNA in J774A.1 macrophages phenocopied that in BMDMs (Supplementary Figure S1), confirming the role of RIP1 in ER stress-induced inflammasome activation in different cell types.
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