Heparin-Binding Protein Enhances NF-κB Pathway-Mediated Inflammatory Gene Transcription in M1 Macrophages via Lactate

In early-stage sepsis, glucose metabolism is increased primarily through glycolysis in the inflammatory response of M1 macrophages. Heparin-binding protein (HBP) has been linked to sepsis, which can promote macrophage activation and inflammatory factor release. However, the mechanism by which glucose metabolism regulates the inflammatory response is unclear. We show that HBP contributes to sepsis by modulating the inflammatory responsevialactate-dependent glycolysis in macrophages. Peritoneal macrophages from BALB/c mouse were treated with lipopolysaccharide (LPS). The expression of M1-related proinflammatory genes was investigated by PCR array. IL-1 beta, iNOS, TNF-alpha, and IL-6 mRNA expression was determined by qRT-PCR. Intracellular lactate levels were measured using lactate assays. Nuclear factor-kappaB (NF-kappa B) activity was determined by electrophoretic mobility shift assays (EMSAs). TNF-alpha levels were measured by qRT-PCR. HBP enhanced inflammatory gene expression in mouse peritoneal macrophages and intracellular lactate accumulation and significantly increased LPS-stimulated NF-kappa B transcriptional activity and TNF-alpha expression through lactate. Lactate was essential for the HBP-induced increase in LPS-stimulated TNF-alpha expression. The critical role of lactate in HBP-induced NF-kappa B signaling was confirmed, as alpha-CHCA-mediated (MCT) suppression significantly inhibited NF-kappa B activity and TNF-alpha expression. HBP plays an important role in the initial inflammatory reaction, presumably by activating M1 macrophages, increasing lactate levels, and regulating proinflammatory factor releaseviaNF-kappa B pathway activation.

Automated summary

Heparin-binding protein (HBP) modulates the inflammatory response in sepsis by regulating lactate-dependent glycolysis in macrophages, increasing NF-κB pathway activation and TNF-α expression. This mechanism plays a crucial role in the initial inflammatory reaction, highlighting the importance of lactate in regulating proinflammatory factor release.