Lysosomal Fe2+ influx through MCOLN1 channel prevents sustained inflammation by limiting PHDs-regulated NFKB activation in macrophages.

Autophagy Pub Date : 2025-06-01 Epub Date: 2025-02-19 DOI:10.1080/15548627.2025.2465396
Meng-Meng Wang, Wuyang Wang, Jiansong Qi
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Abstract

Lysosomes are best known for their involvement in inflammatory responses, where they participate in the macroautophagy/autophagy process to eliminate inflammasomes. Recently, we have identified a previously overlooked function of lysosomes in regulating macrophage inflammatory responses. Specifically, lysosomes finely control the production of IL1B (interleukin 1 beta) by manipulating the release of lysosomal Fe2+ through MCOLN1. Mechanistically, reactive oxygen species (ROS), accumulated during sustained inflammation in macrophages, cause activation of the MCOLN1, a lysosomal cationic channel. The activation of MCOLN1 triggers the release of lysosomal Fe2 toward the cytosol, which in turn activates prolyl hydroxylase domain enzymes (PHDs). PHDs' activation represses the transcriptional regulator NFKB/NF-kB (nuclear factor kappa B) activity by restraining RELA/p65 in the cytosol, leading to decreased IL1B transcription in macrophages. Consequently, the property of controlling production and subsequent release of IL1B from macrophages allows the lysosome to finely restrict sustained inflammatory responses. These findings demonstrate that apart from relying on its degradative capability, the lysosome also limits excessive inflammatory responses to facilitate the restoration of cellular and tissue homeostasis in macrophages by modulating the release of lysosomal Fe2+ through MCOLN1. Even more, by suppressing IL1B production, in vivo stimulation of the MCOLN1 channel alleviates multiple clinical symptoms of dextran sulfate sodium (DSS)-induced colitis in mice, highlighting MCOLN1 as a promising therapeutic target for inflammatory bowel disease (IBD) in clinical settings.

通过MCOLN1通道的溶酶体Fe2+内流通过限制博士调节的巨噬细胞中NFKB的激活来阻止持续的炎症。
溶酶体以参与炎症反应而闻名,它们参与巨噬/自噬过程以消除炎症小体。最近,我们发现了一种以前被忽视的溶酶体在调节巨噬细胞炎症反应中的功能。具体来说,溶酶体通过MCOLN1操纵溶酶体Fe2+的释放,精细地控制il - 1b(白细胞介素1 β)的产生。从机制上讲,在巨噬细胞持续炎症过程中积累的活性氧(ROS)导致溶酶体阳离子通道MCOLN1的激活。MCOLN1的激活触发溶酶体向细胞质释放Fe2,进而激活脯氨酸羟化酶结构域酶(PHDs)。phd的激活通过抑制胞浆中的RELA/p65抑制转录调节因子NFKB/NF-kB(核因子κ B)活性,导致巨噬细胞中IL1B转录降低。因此,控制巨噬细胞产生和随后释放IL1B的特性使溶酶体能够精细地限制持续的炎症反应。这些发现表明,除了依靠其降解能力外,溶酶体还通过MCOLN1调节溶酶体Fe2+的释放,从而限制过度的炎症反应,促进巨噬细胞中细胞和组织稳态的恢复。更重要的是,通过抑制IL1B的产生,在体内刺激MCOLN1通道减轻了小鼠葡聚糖硫酸钠(DSS)诱导的结肠炎的多种临床症状,突出了MCOLN1在临床环境中作为炎症性肠病(IBD)有希望的治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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