Luteolin attenuates Talaromyces marneffei-induced bone destruction by alleviating NLRP3-mediated osteoblast pyroptosis via TNF-α/NF-κB pathway inhibition.

Abstract

Talaromyces marneffei (T. marneffei), an opportunistic pathogen, mainly infects immunocompromised individuals and often causes osteolytic bone destruction. We designed the current study to investigate the therapeutic efficacy and intrinsic mechanism of luteolin (Lut) on T. marneffei-associated osteolysis. The potential therapeutic targets of luteolin were identified by RNA sequencing (RNA-Seq) and network pharmacology methods. GO (gene Ontology), KEGG (Kyoto Encyclopedia of Genes and Genomes), and GSEA (Gene Set Enrichment Analysis) enrichment analyses were used to reveal the molecular mechanism and related pathways. A mouse model of osteolysis induced by T. marneffei and an in vitro infection model were employed to validate the therapeutic efficacy of Lut, and to investigate the regulatory function of Lut in osteogenesis as well as NLRP3 (NLR family pyrin domain containing 3)-mediated pyroptosis. RNA-seq showed differential expressions of nuclear factor-kappa B (NF-κB) and NLRP3-related pyroptosis genes after T. marneffei infection. Network pharmacology identified tumor necrosis factor-α (TNF-α) as a key target. Enrichment analyses highlighted the roles of TNF, NF-κB, and NOD-like receptor (NLR) signaling pathways. In vivo, Lut alleviated bone destruction by suppressing TNF-α-mediated NF-κB signaling, reducing mitochondrial damage, and alleviating NLRP3-mediated osteoblast pyroptosis. In vitro, Lut downregulated TNF-α to inhibit NF-κB signaling, attenuated NLRP3-mediated osteoblast pyroptosis and intracellular reactive oxygen species (ROS) accumulation and promoted osteogenic capacity. In conclusion, Lut inhibits the TNF-α/NF-κB pathway to alleviate NLRP3-mediated osteoblast pyroptosis and maintain osteogenic capacity, showing great potential in treating T. marneffei-induced bone destruction.