Particle uptake by macrophages triggers bifurcated transcriptional pathways that differentially regulate inflammation and lysosomal gene expression.

Exposure to physical particles is a driver of several inflammatory diseases. Here, we systematically investigated responses of macrophages to pathogenic forms of monosodium urate crystals, calcium pyrophosphate crystals, aluminium salts, and silica nanoparticles. While each particle induced a distinct pattern of gene expression, we also identified a common signature that was preferentially linked to inflammation and acute activation of genes required for lysosomal acidification. Using monosodium urate crystals as a model system, we obtained evidence that the program of lysosomal gene expression was regulated by a network of transcription factors that included TFEB and TFE3 and the epigenetic regulators DNMT3A and DOT1L. This lysosomal acidification network operated in parallel with, but largely independently of, a JNK and AP-1 dependent transcription factor network that drove crystal induced chemokine and cytokine gene expression. Mechanistically, the uptake of particles led to early activation of AMPK signalling that was required for activation of TFEB and TFE3 in a process independent of reduced mTOR signalling. These results thereby revealed a mechanism by which the functions of TFEB and TFE3 can be preferentially targeted to specific aspects of lysosomal gene expression, which may provide insights into therapeutic approaches to treat individuals with particle-associated diseases.