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• Quercetin inhibits inflammation by enhancing M2 polarization in macrophages. • Quercetin promotes TRPM2 dependent Ca2+ influx to enhance M2 macrophages. • Quercetin induces Ca2+ dependent AMPK-ATF3 activation to enhance M2 macrophages. • Quercetin upregulates M2 macrophages and improves survival in murine sepsis. M2 macrophage polarization plays a crucial role in counteracting inflammatory disorders such as sepsis. Quercetin is a dietary flavonoid that possesses robust anti-inflammatory properties. However, it is not known whether quercetin takes effects by directly promoting M2 polarization in macrophages. In this study, we observed that quercetin enhanced macrophage M2 polarization and exerted anti-inflammatory activity in LPS stimulated murine peritoneal macrophages. Moreover, quercetin triggered TRPM2 dependent calcium influx and induced calcium dependent activation of AMPKα and ATF3, both were required to mediate M2 macrophage polarization and facilitate the anti-inflammatory activity by quercetin. In a murine endotoxaemia model, quercetin improved survival and ameliorated acute lung injury. Quercetin also induced AMPKα phosphorylation, upregulated ATF3 expression and promoted M2 macrophage polarization in model mice. In conclusion, our results suggest that quercetin promotes macrophage M2 polarization and confers protection of murine sepsis by inducing calcium dependent activation of the AMPK-ATF3 pathway. [ABSTRACT FROM AUTHOR]

Gold nanoparticles (AuNPs) are extensively utilized in biomedical fields. However, their potential interaction with host cells has not been comprehensively elucidated. In this study, we demonstrated a size-dependent effect of AuNPs to synergize with bacterial lipopolysaccharide (LPS) in promoting neutrophil extracellular traps (NETs) release in human peripheral neutrophils. Mechanistically, LPS was more efficient to contact with 10 nm AuNPs and promote their uptake in neutrophils compared to 40 and 100 nm AuNPs, leading to a synergistic upregulation of class A scavenger receptor (SRA) which mediated AuNPs uptake and triggered activation of extracellular regulated protein kinase (ERK) and p38. Blocking SRA or inhibiting ERK and p38 activation remarkably abrogated the effect of AuNPs and LPS to induce NETs formation. Further experiments demonstrated that AuNPs and LPS augmented the production of cytosolic reactive oxygen species (ROS) in p38 and ERK dependent manner, through upregulating and activating NADPH oxidase 2 (NOX2). Accordingly, scavenging of ROS or inhibiting the NOX2 dampened NETs release induced by combined AuNPs and LPS treatment. AuNPs and LPS also synergized to upregulate reactive oxygen species modulator 1 (ROMO1) via activating ERK, thereby increasing mitochondrial ROS generation and promoting the release of NETs. In summary, we provide new evidences about the synergy of AuNPs and LPS to augment cellular responses in neutrophils, which implicates the need to consider the amplifying effect by pathogenic stimuli when utilizing nanomaterials in infectious or inflammatory conditions. ga1 • AuNPs size dependently synergize with LPS to promote NETs release. • LPS preferentially promotes SRA dependent uptake of 10 nm AuNPs. • AuNPs and LPS increase cytosolic and mitochondrial ROS production to induce NETs. • AuNPs and LPS upregulate ROS generation by activating NOX2 and ROMO1. [ABSTRACT FROM AUTHOR]