Mitochondrial RNA modification rewires macrophage glutamine metabolism to promote septic ARDS

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Introduction and background: We had identified RNA methylation might be essential in the pathogenesis of sepsis, but how RNA m5C modification engage in Septic ARDS remains unexplored. Aims and objectives: This study aims to explore how the methyltransferase NSUN3-mediated RNA m5C in macrophages exacerbates sepsis-induced ARDS. Methods: RNA dot blot and RNA sequencing were first employed seperately to assess the m5C levels and the expression of “writer” in peripheral CD14+ monocytes from septic patients, non-infected critical patients, non-septic infection patients, and healthy controls. Then we examined the effect of macrophage-specific Nsun3 knockout on lung injury in septic mice model. Various assays, including mtROS, mitochondrial activity, and bisulfite RNA sequencing, were used to explore the influence of NSUN3 on the mitochondrial function of macrophages. Metabolomics were further employed to elucidate the role of NSUN3 in mitochondrial metabolism. Results: RNA m5C levels were elevated in sepsis patients and NSUN3 was specifically upregulated in the monocytes of septic ARDS patients and closely associated with excessive inflammatory response and poor outcome. Macrophage-specific Nsun3 deficiency alleviates sepsis-induced lung injury in CLP mice model and mitochondrial tRNAMet m5C levels decreased after LPS stimulation in Nsun3-deficient Raw264.7 cells, while mitochondrial function improved, and the expression of glutamine/α-ketoglutarate increased, further supporting the regulation of gene transcription through JMJD3-mediated H3K27me3 modification. Conclusions: NSUN3 might serve as a target for sepsis induced ARDS by regulating glutamine metabolism of macrophages.

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