Role of the NLRP3 inflammasome in the transient release of IL-1β induced by monosodium urate crystals in human fibroblast-like synoviocytes

Pan

et al. 2017

J Neuroinflammation

BackgroundGout is one of the common inflammatory arthritis which affects many people for inflicting unbearable pain. Macrophage-mediated inflammation plays an important role in gout. The uptake of monosodium urate (MSU) crystals by macrophages can lead to activation of NOD-like receptors containing a PYD 3 (NLRP3) inflammasome, thus accelerating interleukin (IL)-1β production. Reactive oxygen species (ROS) promoted development of the inflammatory process through NLRP3 inflammasome. Our study aimed to find a food-derived compound to attenuate gout pain via the specific inhibition of the NLRP3 inflammasome in macrophages.MethodsCD-1 mice were used to evaluate the degree of pain and the swelling dimension of joints after an intra-articular (IA) MSU injection in the ankle. The murine macrophage cell line Raw 264.7 was used to investigate the effects of procyanidins and the mechanism underlying such effects. Histological analysis was used to measure the infiltration of inflammatory cells. ROS produced from Raw 264.7 cells were evaluated by flow cytometry. Cell signaling was measured by Western blot assay and immunofluorescence.ResultsProcyanidins significantly attenuated gout pain and suppressed ankle swelling. Procyanidins also inhibited MSU-induced activation of the NLRP3 inflammasome and increase of IL-1β. Furthermore, procyanidins decreased ROS levels in Raw 264.7 cells.ConclusionsSuppression of the NLRP3 inflammasome in macrophages contributes to the amelioration of gout pain by procyanidins.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0849-y) contains supplementary material, which is available to authorized users.

Section: Discussionsupporting

confidence: 49%

Grape seed-derived procyanidins alleviate gout pain via NLRP3 inflammasome suppression

Pan

et al. 2017

J Neuroinflammation

“…As IL-37 was identified in the diseased synovial tissue from patients with gouty arthritis, synovial cells containing both MLS and FLS were exposed to MSU in studies in vitro. Our previous study revealed that exposure of FLS to MSU crystals only transiently induced an increase in IL-1β expression, which was apparently not sufficient to initiate the inflammatory cascade as seen in resident macrophages [22]. Therefore, besides observing the inhibitory effect of rhIL-37 in vitro, we also hypothesized that MLS may play the role of resident macrophages to initiate inflammation in gouty arthritis.…”

Section: Discussionmentioning

confidence: 95%

Interleukin 37 limits monosodium urate crystal-induced innate immune responses in human and murine models of gout

Zhu

et al. 2016

Arthritis Res Ther

Self Cite

BackgroundInterleukin (IL)-37 has emerged as a fundamental inhibitor of innate immunity. Acute gout is a self-limiting inflammatory response to monosodium urate (MSU) crystals. In the current study, we assessed the preventive and therapeutic effect of recombinant human IL-37 (rhIL-37) in human and murine gout models.MethodsWe investigated the expression of IL-37 in patients with active and inactive gouty arthritis and assessed the effect of rhIL-37 in human and murine gout models: a human monocyte cell line (THP-1) and human synovial cells (containing macrophage-like and fibroblast-like synoviocytes) exposed to MSU crystals, a peritoneal murine model of gout and a murine gouty arthritis model. After inhibition of Mer receptor tyrosine kinase (Mertk), levels of IL-1β, IL-8 and chemokine (C-C motif) ligand 2 (CCL-2) were detected by ELISA and expression of mammalian homologs of the drosophila Mad gene 3 (Smad), suppressor of cytokine signaling 3 (SOCS3), NACHT-LRR-PYD-containing protein 3 (NLRP3), and IL-8R of THP-1 were assessed by qPCR and western blot to explore the molecular mechanisms.ResultsOur studies strongly indicated that rhIL-37 played a potent immunosuppressive role in the pathogenesis of experimental gout models both in vitro and in vivo, by downregulating proinflammatory cytokines and chemokines, markedly reducing neutrophil and monocyte recruitment, and mitigating pathological joint inflammation. In our studies, rhIL-37 suppressed MSU-induced innate immune responses by enhancing expression of Smad3 and IL-1R8 to trigger multiple intracellular switches to block inflammation, including inhibition of NLRP3 and activation of SOCS3. Mertk signaling participated in rhIL-37 inhibitory pathways in gout models. By inhibition of Mertk, the anti-inflammatory effect of rhIL-37 was partly abrogated, and IL-1R8, Smad3 and SOCS3 expression were suppressed, whereas NLRP3 expression was reactivated.ConclusionsOur studies reveal that IL-37 limits runaway inflammation initiated by MSU crystal-induced immune responses, partly in a Mertk-dependent fashion. Thus, rhIL-37 has both preventive and therapeutic effects in gouty arthritis.

Journal of Diabetes Research

“…Caspase1 mediated cleavage is the limiting step for processing IL-1 β into its secreted active forms [22]. Previous studies reported the activation of NLRP3/ASC/caspase1 inflammasome culminated in the production of IL-1 β [23]. ASC act as the indispensable adaptor that connects NLRP3 and procaspase1 [24].…”

Section: Discussionmentioning

confidence: 99%

NLRP3 Inflammasome Expression and Signaling in Human Diabetic Wounds and in High Glucose Induced Macrophages

Zhang

Dai

et al. 2017

Introduction. To investigate the contribution and mechanism of NLRP3 inflammasome expression in human wounds in diabetes mellitus and in high glucose induced macrophages. Methods. In the present study, we compared the expression of NLRP3 inflammasome in debridement wound tissue from diabetic and nondiabetic patients. We also examined whether high glucose induces NLRP3 inflammasome expression in cultures THP-1-derived macrophages and the influence on IL-1β expression. Results. The expressions of NLRP3, caspase1, and IL-1β, at both the mRNA and protein level, were significantly higher in wounds of diabetic patients compared with nondiabetic wounds (P < 0.05). High glucose induced a significant increase in NLRP3 inflammasome and IL-1β expression in THP-1-derived macrophages. M1 macrophage surface marker with CCR7 was significantly upregulated after high glucose stimulation. SiRNA-mediated silencing of NLRP3 expression downregulates the expression of IL-1β. Conclusion. The higher expression of NLRP3, caspase1, and secretion of IL-1β, signaling, and activation might contribute to the hyperinflammation in the human diabetic wound and in high glucose induced macrophages. It may be a novel target to treat the DM patients with chronic wound.