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

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.