Roles of the Caspase-11 Non-Canonical Inflammasome in Rheumatic Diseases.

Inflammasomes are intracellular multiprotein complexes that activate inflammatory signaling pathways. Inflammasomes comprise two major classes: canonical inflammasomes, which were discovered first and are activated in response to a variety of pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), and non-canonical inflammasomes, which were discovered recently and are only activated in response to intracellular lipopolysaccharide (LPS). Although a larger number of studies have successfully demonstrated that canonical inflammasomes, particularly the NLRP3 inflammasome, play roles in various rheumatic diseases, including rheumatoid arthritis (RA), infectious arthritis (IR), gouty arthritis (GA), osteoarthritis (OA), systemic lupus erythematosus (SLE), psoriatic arthritis (PA), ankylosing spondylitis (AS), and Sjögren's syndrome (SjS), the regulatory roles of non-canonical inflammasomes, such as mouse caspase-11 and human caspase-4 non-canonical inflammasomes, in these diseases are still largely unknown. Interestingly, an increasing number of studies have reported possible roles for non-canonical inflammasomes in the pathogenesis of various mouse models of rheumatic disease. This review comprehensively summarizes and discusses recent emerging studies demonstrating the regulatory roles of non-canonical inflammasomes, particularly focusing on the caspase-11 non-canonical inflammasome, in the pathogenesis and progression of various types of rheumatic diseases and provides new insights into strategies for developing potential therapeutics to prevent and treat rheumatic diseases as well as associated diseases by targeting non-canonical inflammasomes.

Inflammation, Inflammatory Diseases, and Inflammasomes.

Inflammation represents the innate immune response of the body tissues against invading microbes and cellular danger signals, and, in this way, it is beneficial [...].

Regulatory Roles of Flavonoids in Caspase-11 Non-Canonical Inflammasome-Mediated Inflammatory Responses and Diseases.

Inflammasomes are multiprotein complexes that activate inflammatory responses by inducing pyroptosis and secretion of pro-inflammatory cytokines. Along with many previous studies on inflammatory responses and diseases induced by canonical inflammasomes, an increasing number of studies have demonstrated that non-canonical inflammasomes, such as mouse caspase-11 and human caspase-4 inflammasomes, are emerging key players in inflammatory responses and various diseases. Flavonoids are natural bioactive compounds found in plants, fruits, vegetables, and teas and have pharmacological properties in a wide range of human diseases. Many studies have successfully demonstrated that flavonoids play an anti-inflammatory role and ameliorate many inflammatory diseases by inhibiting canonical inflammasomes. Others have demonstrated the anti-inflammatory roles of flavonoids in inflammatory responses and various diseases, with a new mechanism by which flavonoids inhibit non-canonical inflammasomes. This review discusses recent studies that have investigated the anti-inflammatory roles and pharmacological properties of flavonoids in inflammatory responses and diseases induced by non-canonical inflammasomes and further provides insight into developing flavonoid-based therapeutics as potential nutraceuticals against human inflammatory diseases.

Korean Red Ginseng Saponins Play an Anti-Inflammatory Role by Targeting Caspase-11 Non-Canonical Inflammasome in Macrophages.

We previously reported that Korean red ginseng (KRG) exerts an anti-inflammatory role through inhibiting caspase-11 non-canonical inflammasome in macrophages; however, the components responsible for the anti-inflammatory role remained unclear. This study explored the anti-inflammatory activity of the KRG saponin fraction (KRGSF) in caspase-11 non-canonical inflammasome-activated macrophages. KRGSF inhibited pyroptosis, pro-inflammatory cytokine secretion, and inflammatory mediator production in caspase-11 non-canonical inflammasome-activated J774A.1 cells. A mechanism study revealed that KRGSF-induced anti-inflammatory action was mediated via suppressing the proteolytic activation of caspase-11 and gasdermin D (GSDMD) in caspase-11 non-canonical inflammasome-activated J774A.1 cells. Moreover, KRGSF increased the survival of lethal septic mice. Taken together, these results reveal KRGSF-mediated anti-inflammatory action with a novel mechanism, by inhibiting caspase-11 non-canonical inflammasome in macrophages.

Regulatory Roles of Caspase-11 Non-Canonical Inflammasome in Inflammatory Liver Diseases.

An inflammatory response consists of two consecutive steps: priming and triggering, to prepare and activate inflammatory responses, respectively. The cardinal feature of the triggering step is the activation of intracellular protein complexes called inflammasomes, which provide a platform for the activation of inflammatory signaling pathways. Despite many studies demonstrating the regulatory roles of canonical inflammasomes in inflammatory liver diseases, the roles of newly discovered non-canonical inflammasomes in inflammatory liver diseases are still largely unknown. Recent studies have reported the regulatory roles of the caspase-11 non-canonical inflammasome in inflammatory liver diseases, providing strong evidence that the caspase-11 non-canonical inflammasome may play key roles in the pathogenesis of inflammatory liver diseases. This review comprehensively discusses the emerging roles of the caspase-11 non-canonical inflammasome in the pathogenesis of inflammatory liver diseases, focusing on non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and inflammatory liver injuries and its underlying mechanisms. This review highlights the current knowledge on the regulatory roles of the caspase-11 non-canonical inflammasome in inflammatory liver diseases, providing new insights into the development of potential therapeutics to prevent and treat inflammatory liver diseases by targeting the caspase-11 non-canonical inflammasome.

Editorial of Special Issue "Inflammasomes and Inflammation".

Although inflammation is a host-protective mechanism from infection and cellular danger signals, chronic inflammation is a major risk factor for various human diseases [...].

Editorial of Special Issue "Roles of Inflammasomes and Methyltransferases in Inflammation".

Inflammation is the first line of defense against pathogens and cellular dangers [...].

14-3-3 epsilon is an intracellular component of TNFR2 receptor complex and its activation protects against osteoarthritis.

OBJECTIVES: Osteoarthritis (OA) is the most common joint disease; however, the indeterminate nature of mechanisms by which OA develops has restrained advancement of therapeutic targets. TNF signalling has been implicated in the pathogenesis of OA. TNFR1 primarily mediates inflammation, whereas emerging evidences demonstrate that TNFR2 plays an anti-inflammatory and protective role in several diseases and conditions. This study aims to decipher TNFR2 signalling in chondrocytes and OA. METHODS: Biochemical copurification and proteomics screen were performed to isolate the intracellular cofactors of TNFR2 complex. Bulk and single cell RNA-seq were employed to determine 14-3-3 epsilon (14-3-3ε) expression in human normal and OA cartilage. Transcription factor activity screen was used to isolate the transcription factors downstream of TNFR2/14-3-3ε. Various cell-based assays and genetically modified mice with naturally occurring and surgically induced OA were performed to examine the importance of this pathway in chondrocytes and OA. RESULTS: Signalling molecule 14-3-3ε was identified as an intracellular component of TNFR2 complexes in chondrocytes in response to progranulin (PGRN), a growth factor known to protect against OA primarily through activating TNFR2. 14-3-3ε was downregulated in OA and its deficiency deteriorated OA. 14-3-3ε was required for PGRN regulation of chondrocyte metabolism. In addition, both global and chondrocyte-specific deletion of 14-3-3ε largely abolished PGRN's therapeutic effects against OA. Furthermore, PGRN/TNFR2/14-3-3ε signalled through activating extracellular signal-regulated kinase (ERK)-dependent Elk-1 while suppressing nuclear factor kappa B (NF-κB) in chondrocytes. CONCLUSIONS: This study identifies 14-3-3ε as an inducible component of TNFR2 receptor complex in response to PGRN in chondrocytes and presents a previously unrecognised TNFR2 pathway in the pathogenesis of OA.

Caspase-11 Noncanonical Inflammasome: A Novel Key Player in Murine Models of Neuroinflammation and Multiple Sclerosis.

Inflammasomes are intracellular protein complexes consisting of the pattern recognition receptors and inflammatory molecules in the inflamed cells. In response to various ligands, inflammasomes play a pivotal role to execute the inflammatory responses by inducing the pyroptosis and the secretion of pro-inflammatory cytokines, interleukin (IL)-1ß, and IL-18. Unlike canonical inflammasomes, including NOD-like receptor family inflammasomes, such as NLRP1, NLRP3, NLRC4, and absence in melanoma 2 inflammasomes, noncanonical inflammasomes, such as mouse caspase-11 and human caspase-4/5 were recently discovered, and their roles in the inflammatory responses have been poorly understood. However, emerging studies have been successfully demonstrating the regulatory roles of these noncanonical inflammasomes on inflammatory responses and the pathogenesis of inflammatory/autoimmune diseases. This review summarizes and discusses the recent studies investigating the regulatory roles of the caspase-11 noncanonical inflammasome in neuroinflammation and the pathogenesis of multiple sclerosis (MS), which provides the insight for the validation of caspase-11 noncanonical inflammasome to develop novel and promising therapeutics for MS.

Functional Interplay between Methyltransferases and Inflammasomes in Inflammatory Responses and Diseases.

An inflammasome is an intracellular protein complex that is activated in response to a pathogenic infection and cellular damage. It triggers inflammatory responses by promoting inflammatory cell death (called pyroptosis) and the secretion of pro-inflammatory cytokines, interleukin (IL)-1ß and IL-18. Many types of inflammasomes have been identified and demonstrated to play a central role in inducing inflammatory responses, leading to the onset and progression of numerous inflammatory diseases. Methylation is a biological process by which methyl groups are transferred from methyl donors to proteins, nucleic acids, and other cellular molecules. Methylation plays critical roles in various biological functions by modulating gene expression, protein activity, protein localization, and molecular stability, and aberrant regulation of methylation causes deleterious outcomes in various human diseases. Methylation is a key determinant of inflammatory responses and diseases. This review highlights the current understanding of the functional relationship between inflammasome regulation and methylation of cellular molecules in inflammatory responses and diseases.

Flavonoids: Nutraceuticals for Rheumatic Diseases via Targeting of Inflammasome Activation.

Inflammation, an innate immune response that prevents cellular damage caused by pathogens, consists of two successive mechanisms, namely priming and triggering. While priming is an inflammation-preparation step, triggering is an inflammation-activation step, and the central feature of triggering is the activation of inflammasomes and intracellular inflammatory protein complexes. Flavonoids are natural phenolic compounds predominantly present in plants, fruits, and vegetables and are known to possess strong anti-inflammatory activities. The anti-inflammatory activity of flavonoids has long been demonstrated, with the main focus on the priming mechanisms, while increasing numbers of recent studies have redirected the research focus on the triggering step, and studies have reported that flavonoids inhibit inflammatory responses and diseases by targeting inflammasome activation. Rheumatic diseases are systemic inflammatory and autoimmune diseases that primarily affect joints and connective tissues, and they are associated with numerous deleterious effects. Here, we discuss the emerging literature on the ameliorative role of flavonoids targeting inflammasome activation in inflammatory rheumatic diseases.

Editorial of Special Issue "Regulatory Roles of Inflammasomes in Human Diseases".

Inflammation is an innate immunity protecting the body from pathogens and cellular damages and comprises two steps; 1) priming (preparatory step) and triggering (activation step). The key feature of the triggering step is the activation of inflammasomes that are intracellular protein complexes consisting of pattern recognition receptors and inflammatory molecules. Inflammasomes are activated in response to various ligands, leading to the caspase-1-mediated maturation and secretion of pro-inflammatory cytokines, IL-1ß and IL-18 and the gasdermin D-mediated pyroptosis, an inflammatory form of cell death. Previous studies have demonstrated that inflammasome activation is a key determinant of inflammatory responses and many human diseases; therefore, inflammasomes have been attracted much attention as critical drug targets to prevent and treat various human diseases.

Functional crosstalk between non-canonical caspase-11 and canonical NLRP3 inflammasomes during infection-mediated inflammation.

Inflammation is a part of the body's immune response for protection against pathogenic infections and other cellular damages; however, chronic inflammation is a major cause of various diseases. One key step in the inflammatory response is the activation of inflammasomes, intracellular protein complexes comprising pattern recognition receptors and other inflammatory molecules. The role of the NLRP3 inflammasome in inflammatory responses has been extensively investigated; however, the caspase-11 inflammasome has been recently identified and has been classified as a 'non-canonical' inflammasome, and emerging studies have highlighted its role in inflammatory responses. Because the ligands and the mechanisms for the activation of these two inflammasomes are different, studies to date have separately described their roles, although recent studies have reported the functional cooperation between these two inflammasomes during an inflammatory response. This review discusses the studies investigating the functional crosstalk between non-canonical caspase-11 and canonical NLRP3 inflammasomes in the context of inflammatory responses; moreover, it provides insight for the development of novel anti-inflammatory therapeutics to prevent and treat infectious and inflammatory diseases.

Caspase-11 Non-Canonical Inflammasome: Emerging Activator and Regulator of Infection-Mediated Inflammatory Responses.

Inflammation is a body's protective mechanism to eliminate invading pathogens and cellular damaging signals. The inflammatory response consists of two main consecutive steps-a priming step preparing the inflammatory responses and a triggering step boosting the inflammatory responses. The main feature of the triggering step is the activation of the inflammasome, an intracellular multiprotein complex facilitating the inflammatory responses. The regulatory roles of 'canonical' inflammasomes in the inflammatory responses and diseases have been largely investigated, so far. New types of inflammasomes have been recently discovered and named as 'non-canonical' inflammasomes since their roles to induce inflammatory responses are similar to those of canonical inflammasomes, however, the stimulating ligands and the underlying mechanisms are different. Therefore, a growing number of studies have actively investigated the novel roles of non-canonical inflammasomes in inflammatory responses and diseases. This review summarizes and discusses the recent studies exploring the regulatory roles of caspase-11 non-canonical inflammasome during the inflammatory responses and provides insight into the development of novel therapeutics for infectious and inflammatory diseases by targeting caspase-11 non-canonical inflammasome.

Korean Red Ginseng Plays An Anti-Aging Role by Modulating Expression of Aging-Related Genes and Immune Cell Subsets.

Despite previous reports of anti-aging effects of Korean red ginseng (KRG), the underlying mechanisms remain poorly understood. Therefore, this study investigated possible mechanisms of KRG-mediated anti-aging effects in aged mice. KRG significantly inhibited thymic involution in old mice. Interestingly, KRG only increased protein expression, but not mRNA expression, of aging-related genes Lin28a, GDF-11, Sirt1, IL-2, and IL-17 in the thymocytes of old mice. KRG also modulated the population of some types of immune cells in old mice. KRG increased the population of regulatory T cells and interferon-gamma (IFN-γ)-expressing natural killer (NK) cells in the spleen of old mice, but serum levels of regulatory T cell-specific cytokines IL-10 and TGF-ß were unaffected. Finally, KRG recovered mRNA expression of Lin28a, GDF-11, and Sirt1 artificially decreased by concanavalin A (Con A) in both thymocytes and splenocytes of old mice without cytotoxicity. These results suggest that KRG exerts anti-aging effects by preventing thymic involution, as well as modulating the expression of aging-related genes and immune cell subsets.

The Anti-Cancer Effect of Linusorb B3 from Flaxseed Oil through the Promotion of Apoptosis, Inhibition of Actin Polymerization, and Suppression of Src Activity in Glioblastoma Cells.

Linusorbs (LOs) are natural peptides found in flaxseed oil that exert various biological activities. Of LOs, LOB3 ([1-9-NαC]-linusorb B3) was reported to have antioxidative and anti-inflammatory activities; however, its anti-cancer activity has been poorly understood. Therefore, this study investigated the anti-cancer effect of LOB3 and its underlying mechanism in glioblastoma cells. LOB3 induced apoptosis and suppressed the proliferation of C6 cells by inhibiting the expression of anti-apoptotic genes, B cell lymphoma 2 (Bcl-2) and p53, as well as promoting the activation of pro-apoptotic caspases, caspase-3 and -9. LOB3 also retarded the migration of C6 cells, which was achieved by suppressing the formation of the actin cytoskeleton critical for the progression, invasion, and metastasis of cancer. Moreover, LOB3 inhibited the activation of the proto-oncogene, Src, and the downstream effector, signal transducer and activator of transcription 3 (STAT3), in C6 cells. Taken together, these results suggest that LOB3 plays an anti-cancer role by inducing apoptosis and inhibiting the migration of C6 cells through the regulation of apoptosis-related molecules, actin polymerization, and proto-oncogenes.

Morinda citrifolia noni water extract enhances innate and adaptive immune responses in healthy mice, ex vivo, and in vitro.

Although Morinda citrifolia (noni) has long been used in traditional medicines for human diseases, its molecular and cellular mechanism of immunostimulatory ability to improve human health under normal healthy conditions is not fully elucidated. This study aimed to investigate the in vitro and in vivo immunostimulatory activity of M. citrifolia fruit water extract treated with enzymes (Mc-eWE). In vitro studies revealed that Mc-eWE stimulated the cells by inducing nitric oxide (NO) production and the expression of inflammatory cytokines, such as interleukin (IL)-1ß, IL-6, IL-12, tumor necrosis factor-alpha (TNF-α), and interferon-gamma (IFN-γ). The immunostimulatory activity was mediated by activation of NF-κB and AP-1. Ex vivo studies showed that Mc-eWE stimulated splenocytes isolated from mice by inducing NO production and expression of immunostimulatory cytokines and by downregulating the expression of the immunosuppressive cytokine IL-10 without cytotoxicity. In vivo demonstrated that Mc-eWE induced immunostimulation by modulating populations of splenic immune cells, especially by increasing the population of IFN-γ+ NK cells. Mc-eWE enhanced the expression of inflammatory genes and immunostimulatory cytokines and inhibited the expression of IL-10 in the mouse splenocytes and sera. Taken together, these results suggest that Mc-eWE plays an immunostimulatory role by activating innate and adaptive immune responses.

Tabetri™ (Tabebuia avellanedae Ethanol Extract) Ameliorates Atopic Dermatitis Symptoms in Mice.

Tabebuia avellanedae has been traditionally used as an herbal remedy to alleviate various diseases. However, the plant's pharmacological activity in allergic and inflammatory diseases and its underlying mechanism are not fully understood. Therefore, we investigated the pharmacological activity of Tabetri (T. avellanedae ethanol extract (Ta-EE)) in the pathogenesis of AD. Its underlying mechanism was explored using an AD mouse model and splenocytes isolated from this model. Ta-EE ameliorated the AD symptoms without any toxicity and protected the skin of 2,4-dinitrochlorobenzene- (DNCB-) induced AD mice from damage and epidermal thickness. Ta-EE reduced the secreted levels of allergic and proinflammatory cytokines, including histamine, immunoglobulin E (IgE), interleukin- (IL-) 4, and interferon-gamma (IFN-γ) in the DNCB-induced AD mice. Ta-EE suppressed the mRNA expression of T helper 2-specific cytokines, IL-4 and IL-5, and the proinflammatory cytokine IFN-γ in the atopic dermatitis skin lesions of AD mice. Moreover, Ta-EE suppressed the mRNA expression of IL-4, IL-5, IFN-γ, and another proinflammatory cytokine, IL-12, in the Con A-stimulated splenocytes. It also suppressed IL-12 and IFN-γ in the LPS-stimulated splenocytes. Taken together, these results suggest that Ta-EE protects against the development of AD through the inhibition of mRNA expression of T helper 2-specific cytokines and other proinflammatory cytokines.

Hydroquinone Exhibits In Vitro and In Vivo Anti-Cancer Activity in Cancer Cells and Mice.

Hydroquinone (HQ, 1,4-benzenediol) is a hydroxylated benzene metabolite with various biological activities, including anti-oxidative, neuroprotective, immunomodulatory, and anti-inflammatory functions. However, the anti-cancer activity of HQ is not well understood. In this study, the in vitro and in vivo anti-cancer activity of HQ was investigated in various cancer cells and tumor-bearing mouse models. HQ significantly induced the death of A431, SYF, B16F10, and MDA-MB-231 cells and also showed a synergistic effect on A431 cell death with other anti-cancer agents, such as adenosine-2',3'-dialdehyde and buthionine sulfoximine. In addition, HQ suppressed angiogenesis in fertilized chicken embryos. Moreover, HQ prevented lung metastasis of melanoma cells in mice in a dose-dependent manner without toxicity and adverse effects. HQ (10 mg/kg) also suppressed the generation of colon and reduced the thickness of colon tissues in azoxymethane/dextran sodium sulfate-injected mice. This study strongly suggests that HQ possesses in vitro and in vivo anti-cancer activity and provides evidence that HQ could be developed as an effective and safe anti-cancer drug.

Role of inflammasomes in inflammatory autoimmune rheumatic diseases.

Inflammasomes are intracellular multiprotein complexes that coordinate anti-pathogenic host defense during inflammatory responses in myeloid cells, especially macrophages. Inflammasome activation leads to activation of caspase-1, resulting in the induction of pyroptosis and the secretion of pro-inflammatory cytokines including interleukin (IL)-1ß and IL-18. Although the inflammatory response is an innate host defense mechanism, chronic inflammation is the main cause of rheumatic diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), ankylosing spondylitis (AS), and Sjögren's syndrome (SS). Since rheumatic diseases are inflammatory/autoimmune disorders, it is reasonable to hypothesize that inflammasomes activated during the inflammatory response play a pivotal role in development and progression of these diseases. Indeed, previous studies have provided important observations that inflammasomes are actively involved in the pathogenesis of inflammatory/autoimmune rheumatic diseases. In this review, we summarize the current knowledge on several types of inflammasomes during macrophage-mediated inflammatory responses and discuss recent research regarding the role of inflammasomes in the pathogenesis of inflammatory/autoimmune rheumatic diseases. This avenue of research could provide new insights for the development of promising therapeutics to treat inflammatory/autoimmune rheumatic diseases.