Shionone Alleviates Sepsis-Induced Acute Lung Injury by Regulating Macrophage Polarization Through the HMGB1/NF-κB Pathway.

BACKGROUND: Sepsis-induced acute lung injury (ALI) poses a significant therapeutic challenge due to the lack of effective treatments. Shionone (SHI), a compound known for its anti-inflammatory properties, was investigated for its potential to mitigate ALI by modulating macrophage polarization, a key process in the inflammatory response. The underlying mechanism was also explored. METHODS: using lung histopathology (hematoxylin and eosin H&E staining) and the lung wet-to-dry weight ratio. Cell viability was assessed using a Cell Counting Kit-8 (CCK-8) assay. The levels of inflammatory cytokines (interleukin-6 IL-6, interleukin-1 beta IL-1β, tumor necrosis factor-alpha TNF-α, granulocyte-macrophage colony-stimulating factor GM-CSF, Interleukin-10 IL-10, transforming growth factor-beta 1 TGF-β1) and polarization markers (inducible nitric oxide synthase iNOS, arginase-1 Arg1) were quantified by enzyme-linked immunosorbent assay ELISA and real-time quantitative PCR. The expression of key proteins in the high-mobility group box 1 (HMGB1)/nuclear factor κ B (NF-κB) pathway (HMGB1, toll-like receptor 4 TLR4, myeloid differentiation primary response 88 MyD88, NF-κB p65) was analyzed by western blot and immunofluorescence. The study used a small interfering RNA siRNA loss-of-function strategy to demonstrate that HMGB1 is a critical target of SHI. RESULTS: models, SHI suppressed the production of pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) and the M1 macrophage marker iNOS, while enhancing the release of anti-inflammatory cytokines (GM-CSF, IL-10, TGF-β1) and the M2 marker Arg1. Mechanistically, SHI inhibited the activation of the HMGB1/NF-κB pathway by downregulating the expression of HMGB1, TLR4, MyD88, and NF-κB phosphorylation. The critical role of HMGB1 was further supported by the finding that siRNA-mediated knockdown of HMGB1 mimicked the anti-inflammatory and polarization-shifting effects induced by SHI. CONCLUSION: Our findings demonstrate that SHI alleviates sepsis-induced ALI by reprogramming macrophage polarization from a pro-inflammatory M1 phenotype to an anti-inflammatory M2 phenotype. This protective effect is primarily mediated through the inhibition of the HMGB1/NF-κB signaling pathway. Thus, SHI represents a potential therapeutic candidate for sepsis-associated lung injury.