| 著者 |
Cobo I, Murillo-Saich J, Alishala M, Calderon S, Coras R, Hemming B, Inkum F, Rosas F, Takei R, Spann N, Prohaska TA, Alabarse PVG, Jeong SJ, Nickl CK, Cheng A, Li B, Vogel A, Weichhart T, Fuster JJ, Le T, Bradstreet TR, Webber AM, Edelson BT, Razani B, Ebert BL, Taneja R, Terkeltaub R, Bryan RL, Guma M, Glass CK.
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| Abstract |
Exposure to particles is a driver of several inflammatory diseases. Here, we investigated macrophage responses to monosodium urate crystals, calcium pyrophosphate crystals, aluminum salts, and silica nanoparticles. While each particle induced a distinct gene expression pattern, we identified a common inflammatory signature and acute activation of lysosomal acidification genes. Using monosodium urate crystals as a model, we demonstrated that this lysosomal gene program is regulated by a 5'-prime-AMP-activated protein kinase (AMPK)-dependent transcriptional network, including TFEB, TFE3, and the epigenetic regulators DNA methyl transferase 3a (DNMT3A) and DOT1L. This lysosomal acidification program operates in parallel with, but largely independently of, a JNK-AP-1-dependent network driving crystal-induced chemokine and cytokine expression. These findings reveal a bifurcation in pathways governing inflammatory and lysosomal responses, offering insights for treating particle-associated diseases.
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