Inhibition of inflammasome activation improves the impaired pattern of healing in genetically diabetic mice

Background and Purpose

Type 2 diabetes impairs the healing process because of an exaggerated and persistent inflammatory response, and an altered expression pattern of angiogenic molecules. We investigated the effects of inflammasome blockade in diabetes-related wound-healings defects, in genetically diabetic mice.

Experimental Approach

An incisional skin wound model was produced on the back of female diabetic C57BL/KsJ-m +/+ Lept^db mice (db⁺/db⁺) and their normal littermates (db⁺/m⁺). Animals were treated daily with two inflammasome blocking agents, BAY 11-7082 (20 mg·kg⁻¹ i.p.), or Brilliant Blue G (BBG, 45.5 mg·kg⁻¹ i.p.), or vehicle. Mice were killed on 3, 6 and 12 days after skin injury to measure expression of the NOD-like receptor NLRP3, caspase-1, VEGF, the inflammasome adapter protein apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and the chemokine CXCL12. Wound levels of IL-1β and IL-18 were also measured, along with histological assessments of wound tissue and the time to complete wound closure.

Key Results

During healing, the diabetic mice exhibited increased activation of NLRP3, caspase-1, ASC, IL-1β and IL-18. They also showed a reduced expression of VEGF and CXCL12.Treatment with BAY 11-7082 or BBG, to block activation of the inflammasome, decreased the levels of pro-inflammatory molecules. Histological evaluation indicated that inflammasome blockade improved the impaired healing pattern, at day 12 in diabetic mice, along with a decreased time to complete skin healing.

Conclusions and Implications

These data strongly suggest that activation of the NLRP3 inflammasome is one of the key contributors to the delayed healing of wounds in diabetic mice.     

IL-18: a new player in immunotherapy for age-related macular degeneration?

Recent evidence suggests that the pro-inflammatory cytokine IL-18 may have utility as an anti-angiogenic agent in the eye. Numerous laboratories, including our own have demonstrated the ability of murine IL-18 to prevent neovascularization in the retina, choroid and cornea in pathological scenarios. Here, we summarize the potential use of IL-18 as an immunotherapy for wet age-related macular degeneration treatment, describing past and recent findings pertaining to its biological function in the eye.     

A brain in flame; do inflammasomes and pyroptosis influence stroke pathology?

Stroke is one of the leading causes of death and disability worldwide. Inflammation plays a key role across the time course of stroke, from onset to the post‐injury reparative phase days to months later. Several regulatory molecules are implicated in inflammation, but the most established inflammatory mediator of acute brain injury is the cytokine interleukin‐1. Interleukin‐1 is regulated by large, macromolecular complexes called inflammasomes, which play a central role in cytokine release and cell death. In this review we highlight recent advances in inflammasome research and propose key roles for inflammasome components in the progression of stroke damage.     

小胶质细胞自噬和炎症及其交互作用对脑出血调控机制的研究进展

脑出血好发于中老年人,对中老年人健康威胁极大。我国脑出血发病率仅次于脑梗死,是第二大脑卒中类型,且脑出血患者在脑卒中患者中所占比例远高于西方发达国家,这对已步入老龄化的中国社会及患者家庭造成了沉重的负担。目前,临床尚缺乏确切有效的脑出血治疗手段。作为大脑组织的主要吞噬细胞,小胶质细胞在脑出血后脑损伤过程中发挥着重要作用,如通过自噬及调节炎症发挥中枢神经系统保护作用、减轻脑损伤等。本文综述了小胶质细胞自噬和炎症及其交互作用对脑出血的调控机制,旨在为脑出血的诊疗、新治疗靶点的发现及预后改善等提供参考。     

NLRP3炎症小体在动脉粥样硬化中的作用机制和靶向炎症治疗的研究进展

动脉粥样硬化(As)是由一系列复杂因素引起的病理过程,包括内皮功能障碍、动脉血管壁中脂质沉积、巨噬细胞浸润、平滑肌细胞功能失调、泡沫细胞形成等,炎症反应在这一过程中发挥了重要的作用。NOD样受体热蛋白结构域相关蛋白3(NLRP3)炎症小体是炎症细胞的传导器,其激活后介导炎症反应,激活下游的白细胞介素18、白细胞介素1β,从而参与As的发生和发展。因此,针对NLRP3炎症小体和下游炎症因子的特异性抑制剂是目前临床药物研究的潜在靶点,有望成为治疗As的一种新的治疗措施。文章对NLRP3炎症小体的结构和激活机制及与As的关系进行了讨论,同时对靶向NLRP3炎症小体和下游炎症因子的药物进行了介绍。     

Historical aspects of studies on roles of the inflammasome in the pathogenesis of periodontal diseases

The proinflammatory cytokine interleukin‐1β (IL‐1β) is produced as inactive proIL‐1β and then processed by caspase‐1 to become active. In 2002, it was demonstrated that the intracellular multiprotein complex known as the inflammasome functions as a molecular platform to trigger activation of caspase‐1. Inflammasomes are known to function as intracellular sensors for a broad spectrum of various pathogen‐associated and damage‐associated molecular patterns. In 1985, it was demonstrated that Porphyromonas gingivalis, a representative bacterium causing chronic periodontitis, induces IL‐1 production by murine peritoneal macrophages. Since then, many studies have suggested that IL‐1, particularly IL‐1β plays key roles in the pathogenesis of periodontal diseases. However, the term “inflammasome” was not used until the involvement of inflammasomes in periodontal disease was suggested in 2009. Several subsequent studies on the roles of the inflammasome in the pathogenesis of periodontal diseases have been published. Interestingly, two contradictory reports on the modulation of inflammasomes by P. gingivalis have been published. Some papers have described how P. gingivalis activates the inflammasome to produce IL‐1β whereas some stated that P. gingivalis inhibits inflammasome activation to subvert immune responses. Several lines of evidence have suggested that the inflammasome activation is modulated by periodontopathic bacteria other than P. gingivalis. Hence, studies on the roles of inflammasomes in the pathogenesis of periodontal diseases began only 8 years ago and many pathological roles of inflammasomes remain to be clarified.     

Inflammasomes: guardians of cytosolic sanctity

Summary:  The innate immune system is critical in recognizing bacterial and viral infections to evoke a proper immune response. Certain members of the intracellular nucleotide-binding and oligomerization domain (NOD)-like receptor (NLR) family detect microbial components in the cytosol and trigger the assembly of large caspase-1-activating complexes termed inflammasomes. Autoproteolytic maturation of caspase-1 zymogens within these inflammasomes leads to maturation and secretion of the pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18. The NLR proteins ICE protease-activating factor (IPAF), NALP1b (NACHT domain-, leucine-rich repeat-, and PYD-containing protein 1b), and cryopyrin/NALP3 assemble caspase-1-activating inflammasomes in a stimulus-dependent manner. Bacterial flagellin is sensed by IPAF, whereas mouse NALP1b detects anthrax lethal toxin. Cryopyrin/NALP3 mediates caspase-1 activation in response to a wide variety of microbial components and in response to crystalline substances such as the endogenous danger signal uric acid. Genetic variations in Nalp1 and cryopyrin/Nalp3 are associated with autoinflammatory disorders and increased susceptibility to microbial infection. Further understanding of inflammasomes and their role in innate immunity should provide new insights into the mechanisms of host defense and the pathogenesis of autoimmune diseases.     

Tetrahydroxy Stilbene Glucoside Alleviates High Glucose-Induced MPC5 Podocytes Injury Through Suppression of NLRP3 Inflammasome

Background

Tetrahydroxy stilbene glucoside (TSG) is an active ingredient of Heshouwu and is an antioxidant. The underlying mechanisms of the renoprotective effect of TSG in diabetic nephropathy have not been previously reported. In this study, we investigated the mechanisms of TSG in preventing podocytes injury in high glucose (HG) condition.