Article Impact Level: HIGH Data Quality: STRONG Summary of Immunity, 58(4), 826-842.e8. https://doi.org/10.1016/j.immuni.2025.02.023 Dr. Isidoro Cobo et al.
Points
- Transcriptomic analysis showed that diverse particles activate a common set of 313 genes in macrophages, primarily driving inflammation and essential lysosomal acidification processes.
- The study demonstrates that this macrophage activation involves a bifurcation of signaling into two functionally distinct and largely independent transcriptional networks that control inflammation and lysosomal function separately.
- A newly identified AMPK-TFEB/TFE3 signaling axis, which recruits the epigenetic regulators DOT1L and DNMT3A, was found to drive the expression of genes vital for lysosomal repair specifically.
- In contrast, the pro-inflammatory response involving cytokine and chemokine production is independently governed by the parallel JNK-AP-1 signaling pathway, confirming its distinct and separate regulatory control.
- This functional segregation of pathways presents a novel therapeutic strategy for selectively inhibiting pathological inflammation while preserving the macrophage’s
Summary
A study investigated the transcriptional programs governing macrophage responses to pathogenic particles implicated in gout and silicosis, including monosodium urate crystals (MSUc), calcium pyrophosphate crystals, silica nanoparticles, and aluminum salts. Following a five-hour particle exposure, transcriptomic analysis of mouse macrophages revealed significant gene expression changes, with 841 to 2,275 genes upregulated and 781 to 1,835 genes downregulated, depending on the particle type. A core transcriptional signature was identified across all stimuli, comprising 313 commonly upregulated genes enriched for inflammatory signaling and lysosomal function, particularly acidification, along with 131 commonly downregulated genes, indicating a conserved response mechanism.
Mechanistic investigation using MSUc as a model revealed a bifurcation of downstream signaling pathways. The study demonstrated that the expression of lysosomal acidification genes is regulated by a novel axis involving 5′-prime-AMP-activated protein kinase (AMPK) signaling, which activates the transcription factors TFEB and TFE3. This process requires the recruitment of the epigenetic regulators DOT1L and DNA methyltransferase 3a (DNMT3A), with DNMT3A functioning independently of its canonical DNA methylation activity. In parallel, the induction of inflammatory cytokines and chemokines was confirmed to be driven by a distinct and largely independent JNK-AP-1 signaling pathway.
These findings support a model wherein particle phagocytosis triggers two distinct transcriptional networks. The AMPK-TFEB/TFE3-DOT1L/DNMT3A axis specifically directs the lysosomal acidification and repair program, while the JNK-AP-1 pathway mediates the pro-inflammatory response separately. This functional segregation of lysosomal integrity and inflammatory gene expression offers a refined understanding of macrophage activation in particle-associated diseases. The discovery of this bifurcated regulation suggests that these pathways could be targeted independently, presenting a potential therapeutic strategy to suppress pathological inflammation while preserving essential lysosomal clearance functions selectively.
Link to the article: https://www.cell.com/immunity/abstract/S1074-7613(25)00090-1
References Cobo, I., Murillo-Saich, J., Alishala, M., Calderon, S., Coras, R., Hemming, B., Inkum, F., Rosas, F., Takei, R., Spann, N., Prohaska, T. A., Alabarse, P. V. G., Jeong, S.-J., Nickl, C. K., Cheng, A., Li, B., Vogel, A., Weichhart, T., Fuster, J. J., … Glass, C. K. (2025). Particle uptake by macrophages triggers bifurcated transcriptional pathways that differentially regulate inflammation and lysosomal gene expression. Immunity, 58(4), 826-842.e8. https://doi.org/10.1016/j.immuni.2025.02.023
