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Gout, the most prevalent inflammatory arthritis worldwide, released interleukin-1β (IL-1β) and Cathepsin B inflammatory mediators that constitute the hallmark of the disease. Herein we aimed to investigate whether procyanidin B2 (PCB2), a natural dietary compound, can suppress MSU crystals-stimulated gouty inflammation. Treated with lipopolysaccharide (LPS) plus MSU, both mouse peritoneal macrophages (MPM) and mouse bone marrow-derived macrophages (BMDM) released a large amount of mature IL-1β compared to those treated with MSU or LPS alone, while IL-1β release was blocked by TLR4 and its downstream effector inhibitors. In two mouse models of gout, oral administration of PCB2 suppressed MSU crystals-induced increasing expression of IL-1β, Cathepsin B and NLRP3 in the air pouch skin and paws, accompanied with the downregulation prostaglandin E2 (PGE2) in pouch exudates. Inflammatory immune cell infiltration including macrophages and neutrophils were significantly blocked by PCB2 in air pouch skin and paws of mice gout groups. PCB2 also suppressed the release of IL-1β and Cathepsin B induced by MSU plus LPS in MPM. Our results suggest that the inhibitory effects of PCB2 on NLRP3 inflammasome may alleviate inflammatory response in gout, and this might be a promising anti-inflammatory mechanism of PCB2 against the inflammation in gout.

Background and Purpose: Regulating macrophage-hepatocyte crosstalk through P2X7 receptors has led to new pharmacological strategies to reverse alcoholic hepatosteatosis. We investigated how tetrahydroxystilbene glucoside (2354glu), isolated from Polygonum multiflorum, modulates macrophage-hepatocyte crosstalk during alcoholic hepatosteatosis., Experimental Approach: A model of alcoholic hepatosteatosis was established by giving ethanol intragastrically to C57BL/6 mice. HepG2 cells were incubated in conditioned medium from LPS+ATP-activated THP-1 human macrophages with silenced or overexpressed P2X7 receptors. THP-1 macrophages or mouse peritoneal macrophages were pretreated with 2354glu for 1 hr prior to LPS+ATP stimulation. Western blots, RT-PCR and immunohistochemical analysis were used, along with over-expression and silencing of P2X7 receptors., Key Results: Knockdown or overexpression of P2X7 receptors in THP-1 macrophages affected release of mature IL-1β and, subsequently, modulated lipid metabolism in HepG2 cells via the LKB-AMPK pathway. 2354glu ameliorated alcoholic hepatosteatosis in mice by regulating LKB1-AMPK-SREBP1 pathway and its target genes. Suppression of P2X7 receptor activation by 2354glu inhibited IL-1β release and reduced macrophage and neutrophil infiltration. In macrophages stimulated with LPS+ATP, expression of P2X7 receptors, caspase-1 and NF-κB, release of IL-1β, calcium influx and PI uptake were reduced by 2354glu. SIRT1-LKB1-AMPK-SREBP1 axis-mediated lipid accumulation in HepG2 cells was reduced when they were cultured with conditioned media from LPS+ATP-activated THP-1 macrophages pretreated with 2354glu., Conclusion and Implications: Modulation of P2X7 receptors in macrophages regulated lipid accumulation in hepatocytes during alcoholic hepatosteatosis. 2354glu might be a promising candidate that targets P2X7 receptors in macrophages interacting with hepatocytes during alcoholic hepatosteatosis., (© 2020 The British Pharmacological Society.)

Cryptotanshinone (CTN), one of the major constituents of tanshinones, was investigated for anti-inflammatory activity in the murine macrophage cell line RAW 264.7. CTN inhibited the production of nitric oxide (NO) production, as well as expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) in lipopolysaccharide (LPS)-stimulated macrophages. Since CTN was considered as inhibiting LPS-triggered phosphorylation of mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-κB activation, we consequently evaluated the expression of toll-like receptor 4 (TLR4) and CD14, as well as phosphorylation of TGF-β-activated kinase 1 (TAK1). CTN reduced the expression of CD14 and TLR4, and suppressed LPS-induced phosphorylation of TAK1. Furthermore, CTN significantly increased the survival rate against LPS challenge in D-galactosamine-sensitized mice, which was in line with in vitro results. These results suggested that CD14/TLR4 and TAK1 might be the potential molecular targets for addressing the protective effects of CTN on LPS-induced inflammatory effects in macrophages., (Copyright © 2011 Elsevier B.V. All rights reserved.)

• Blockade of P2x7R with its selective inhibitor, A438079, reverses thioacetamide-induced liver damage and fibrosis via inhibiting P2x7R-NLRP3 inflammasome activation • Ectopic overexpression of P2x7R lowered the threshold of extracellular matrix (ECM) deposition in HSCs • Macrophages stimulated by LPS/ATP aggravated ECM deposition in HSCs through activating P2x7R • IL-1β secreted by LPS/ATP activated macrophages amplifies the fibrosis signal from macrophages HSCs (hepatic stellate cells) contribute to the excessive extracellular matrix (ECM) deposition, inflammatory pathways and crucial cell-cell interactions in hepatic disease leading to fibrosis. P2x7R is considered a potential orchestrater in liver fibrosis. For this reason, this work explored the role of P2x7R in liver fibrosis and the mechanism by which P2x7R in macrophages promotes fibrogenesis. In a model of liver fibrosis induced by administration of thioacetamide (TAA), inhibition of P2x7R with its selective inhibitor A438079 reversed TAA-induced liver damage and fibrosis. The mechanism was linked to inhibition of P2x7R-NLRP3 inflammasome activation and thereby infiltration of macrophages and neutrophils into the liver. This result indicated that the P2x7R-TLR4-NLRP3 axis is involved in the process of TGF-β-mediated ECM deposition in HSCs. Ectopic overexpression of P2x7R lowered the threshold of extracellular matrix (ECM) deposition and maintained HSCs in an activated state. The culture medium of THP-1 macrophages stimulated by LPS/ATP aggravated ECM deposition in HSCs by activating P2x7R. Additionally, IL-1β secreted by LPS / ATP activated macrophages amplified fibrosis. These data indicate that P2x7R plays a key regulative role in the activation and maintenance of HSCs promoted by macrophages. Thus, pharmacological inhibition of P2x7R could be a potential therapeutic mechanism to treat human liver fibrosis. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Leucodin inhibited LPS/ATP-induced IL-1β cleavage in macrophage through P2x7R-NLRP3 axis. • Leucodin inhibited lipid deposition in ethanol-exposed steatotic hepatocytes. • Leucodin might be a promising therapeutic potential targeting inflammation and lipid metabolism in ALD. Abstract The current study was aimed to reveal that leucodin, a sesquiterpene lactone from Artemisia capillaris could inhibit the inflammatory response in macrophages and the lipid accumulation in hepatocytes via P2x7R-NLRP3 inflammasome activation. Several types of macrophages including mouse peritoneal macrophages, mouse bone marrow-derived macrophages and human macrophages THP-1 cells were pretreated with different concentrations of leucodin for 1 h and then stimulated with LPS and ATP. LPS plus ATP initiated IL-1β cleavage and release in mouse peritoneal macrophages and peaked at 4 h. Leucodin did not show significant toxicity within 200 μM and effectively inhibited pro-IL-1β cleavage and release of mature-IL-1β in macrophages. Also, P2x7R antagonist and caspase-1 inhibitor also decreased IL-1β release and cleavage. Additionally, leucodin suppressed P2x7R, TLR4 and NLRP3 expression in LPS/ATP-stimulated macrophages. HepG2 cells were pretreated with different concentrations of leucodin for 1 h and then exposed to ethanol for 24 h. Leucodin suppressed lipid accumulation and enhanced phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) in HepG2 cells exposed to ethanol. In addition, leucodin inhibited the expression of sterol regulatory element binding protein-1 (SREBP1) and ACC in ethanol-treated HepG2 cells. Leucodin possessed the capacity for inhibiting inflammatory response in macrophages and suppressing lipid accumulation in hepatocytes, suggesting a promising therapeutic potential targeting inflammation and lipid metabolism in alcoholic liver disease. [ABSTRACT FROM AUTHOR]