Immunity · 2025
Particle uptake by macrophages triggers bifurcated transcriptional pathways that differentially regulate inflammation and lysosomal gene expression.
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Cobo Isidoro, Murillo-Saich Jessica, Alishala Mohnish, Calderon Stephen, Coras Roxana, Hemming Benjamin, Inkum Faith, Rosas Fiorella, Takei Riku, Spann Nathan, Prohaska Thomas A, Alabarse Paulo V G, Jeong Se-Jin, Nickl Christian K, Cheng Anyan, Li Benjamin, Vogel Andrea, Weichhart Thomas, Fuster José J, Le Thomas, Bradstreet Tara R, Webber Ashlee M, Edelson Brian T, Razani Babak, Ebert Benjamin L, Taneja Reshma, Terkeltaub Robert, Bryan Ru Liu, Guma Monica, Glass Christopher K
Аннотация
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.