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.