Autophagy Controls IL-1β Secretion by Targeting Pro-IL-1β for Degradation
Autophagy Controls IL-1β Secretion by Targeting Pro-IL-1β for Degradation
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DOI：
10.1074/jbc.m110.202911
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发表时间：
2011-03-18
影响因子：
4.8
通讯作者：
Lavelle, Ed C.
中科院分区：
文献类型：
--
作者：
Harris, James;Hartman, Michelle;Lavelle, Ed C.
自噬是细胞内稳态的关键调节因子，可被病原体相关分子激活，最近已显示影响巨噬细胞的IL-1 β分泌。然而，这背后的机制尚不清楚。在这里，我们描述了一个新的作用，自噬在调节生产的IL-1 β在抗原呈递细胞。在用Toll样受体配体处理巨噬细胞后，pro-IL-1 β被特异性地隔离到自噬体中，而用雷帕霉素进一步激活自噬诱导pro-IL-1 β的降解并阻断成熟细胞因子的分泌。自噬的抑制以NLRP 3和TRIF依赖性方式促进抗原呈递细胞对IL-1 β的加工和分泌。这种作用因活性氧簇的抑制而减弱，但与NOX 2无关。在小鼠体内用雷帕霉素诱导自噬降低了响应于用LPS攻击的IL-1 β的血清水平。这些数据表明，自噬通过至少两种不同的机制控制IL-1 β的产生：通过靶向pro-IL-1 β进行溶酶体降解和通过调节NLRP 3炎性体的活化。
Autophagy is a key regulator of cellular homeostasis that can be activated by pathogen-associated molecules and recently has been shown to influence IL-1 beta secretion by macrophages. However, the mechanisms behind this are unclear. Here, we describe a novel role for autophagy in regulating the production of IL-1 beta in antigen-presenting cells. After treatment of macrophages with Toll-like receptor ligands, pro-IL-1 beta was specifically sequestered into autophagosomes, whereas further activation of autophagy with rapamycin induced the degradation of pro-IL-1 beta and blocked secretion of the mature cytokine. Inhibition of autophagy promoted the processing and secretion of IL-1 beta by antigen-presenting cells in an NLRP3- and TRIF-dependent manner. This effect was reduced by inhibition of reactive oxygen species but was independent of NOX2. Induction of autophagy in mice in vivo with rapamycin reduced serum levels of IL-1 beta in response to challenge with LPS. These data demonstrate that autophagy controls the production of IL-1 beta through at least two separate mechanisms: by targeting pro-IL-1 beta for lysosomal degradation and by regulating activation of the NLRP3 inflammasome.