• Drug delivery
• Etiology
• Interleukin-1
• Interleukin-1 receptor antagonist

• Humans
• Drug Delivery Systems
• Animals
• Interleukin 1 Receptor Antagonist Protein/administration & dosage
• Interleukin 1 Receptor Antagonist Protein/therapeutic use

• Gout/diagnosis
• Gout/drug therapy
• Gout/etiology
• Metabolic Syndrome/blood
• Metabolic Syndrome/complications
• Metabolic Syndrome/diagnosis
• Humans
• Cardiovascular Diseases/etiology
• Uric Acid/blood
• Hyperuricemia/blood
• Hyperuricemia/drug therapy
• Hyperuricemia/etiology
• Risk
• Losartan/therapeutic use
• Calcium Channel Blockers/therapeutic use
• Anti-Inflammatory Agents/therapeutic use
• Antihypertensive Agents/therapeutic use

• Comprehensive nursing intervention
• Elderly
• Gout and hyperuricemia
• Hypertensive complications
• Outcomes
• Treatment

• Comprehensive Nursing Intervention
• Elderly Patients
• Hypertension
• Hyperuricemia

• Immune response
• Immunity
• Immunology
• Molecular biology
• Omics
• Transcriptomics

• Anakinra
• Canakinumab
• Gout flare
• Interleukin-1β
• Randomised controlled trials
• Rilonacept

• Albumin-binding domain
• Gout
• IL-1Ra
• Uric acid
• Uricase

• Consensus
• Gout
• Hong Kong Society of Rheumatology
• Hyperuricemia
• Recommendations

• Immunity
• Inflammasome
• NLRP3
• Pyroptosis
• Tumor microenvironment

• Humans
• Inflammasomes
• Tumor Microenvironment
• Interleukin-1
• Inflammation

• No. 32122052 National Science Fund for Excellent Young Scholars
• No. U19A2003 National Natural Science Foundation Regional Innovation and Development

• Anakinra
• Calcium pyrophosphate
• Crystal-associated arthritis
• Pseudogout

• IL-1 blockade
• IL-1 blocking agents
• IL-1 inhibition
• anakinra
• biological therapies
• gout
• gout flare
• gouty arthritis

• allopurinol
• anakinra
• clinical inertia
• febuxostat
• gout
• guidelines
• treat-to-target
• urate-lowering therapy

• Gout
• Inflammasome
• Interleukin-1
• Monosodium urate
• NLRP3

Innovative solutions are needed for the treatment of bacterial infections, and a range of antibacterial molecules have been explored as alternatives to antibiotics. A different approach is to investigate the immune system of the host for new ways of making the antibacterial defence more efficient. However, the immune system has a dual role as protector and cause of disease: in addition to being protective, increasing evidence shows that innate immune responses can become excessive and cause acute symptoms and tissue pathology during infection. This role of innate immunity in disease suggests that the immune system should be targeted therapeutically, to inhibit over-reactivity. The ultimate goal is to develop therapies that selectively attenuate destructive immune response cascades, while augmenting the protective antimicrobial defence but such treatment options have remained underexplored, owing to the molecular proximity of the protective and destructive effects of the immune response. The concept of innate immunomodulation therapy has been developed successfully in urinary tract infections, based on detailed studies of innate immune activation and disease pathogenesis. Effective, disease-specific, immunomodulatory strategies have been developed by targeting specific immune response regulators including key transcription factors. In acute pyelonephritis, targeting interferon regulatory factor 7 using small interfering RNA or treatment with antimicrobial peptide cathelicidin was protective and, in acute cystitis, targeting overactive effector molecules such as IL-1β, MMP7, COX2, cAMP and the pain-sensing receptor NK1R has been successful in vivo. Furthermore, other UTI treatment strategies, such as inhibiting bacterial adhesion and vaccination, have also shown promise.

Hyperactivation of innate immunity is a disease determinant in urinary tract infections (UTIs). Modulation of innate immunity has promise as a therapy for UTIs. In this Review, the authors discuss potential mechanisms and immunomodulatory therapeutic strategies in UTIs.

Excessive innate immune responses to infection cause symptoms and pathology in acute pyelonephritis and acute cystitis.

• Antirheumatic Agents/therapeutic use
• Crystal Arthropathies
• Female
• Gout/drug therapy
• Hospitalization
• Humans
• Interleukin 1 Receptor Antagonist Protein/adverse effects
• Interleukin-1
• Male
• Middle Aged
• Treatment Outcome

Inflammasomes sense intracellular clues of infection, damage, or metabolic imbalances. Activated inflammasome sensors polymerize the adaptor ASC into micron‐sized “specks” to maximize caspase‐1 activation and the maturation of IL‐1 cytokines. Caspase‐1 also drives pyroptosis, a lytic cell death characterized by leakage of intracellular content to the extracellular space. ASC specks are released among cytosolic content, and accumulate in tissues of patients with chronic inflammation. However, if extracellular ASC specks contribute to disease, or are merely inert remnants of cell death remains unknown. Here, we show that camelid‐derived nanobodies against ASC (VHH_ASC) target and disassemble post‐pyroptotic inflammasomes, neutralizing their prionoid, and inflammatory functions. Notably, pyroptosis‐driven membrane perforation and exposure of ASC specks to the extracellular environment allowed VHH_ASC to target inflammasomes while preserving pre‐pyroptotic IL‐1β release, essential to host defense. Systemically administrated mouse‐specific VHH_ASC attenuated inflammation and clinical gout, and antigen‐induced arthritis disease. Hence, VHH_ASC neutralized post‐pyroptotic inflammasomes revealing a previously unappreciated role for these complexes in disease. VHH_ASC are the first biologicals that disassemble pre‐formed inflammasomes while preserving their functions in host defense.

• arthritis
• extracellular inflammasomes
• gout
• nanobodies
• pyroptosis

• NETosis
• apoptosis
• gout
• inflammation
• necroptosis
• programmed cell death
• pyroptosis

• Arthritis, Gouty/metabolism
• Gout/metabolism
• Humans
• Inflammasomes/metabolism
• Macrophages
• Pyroptosis

• Anti-IL-1
• Biologic
• Calcium pyrophosphate crystal deposition
• Crystal-associated arthritis
• Gout

Background: Gouty arthritis (GA) is a common metabolic disease caused by a long-term disorder of purine metabolism and increased serum levels of uric acid. The processed product of dried root of Aconitum carmichaeli Debeaux (Aconiti Radix cocta, ARC) is used often in traditional Chinese medicine (TCM) to treat GA, but its specific active components and mechanism of action are not clear.

Methods: First, we used ultra-performance liquid chromatography-quadrupole/time-of-flight tandem mass spectrometry to identify the chemical spectrum of ARC. Based on this result, we explored the active components of ARC in GA treatment and their potential targets and pathways. Simultaneously, we used computer simulations, in vitro cell experiments and animal experiments to verify the prediction results of systems pharmacology. In vitro, we used aurantiamide acetate (AA) to treat monosodium urate (MSU)-stimulated THP-1 cells and demonstrated the reliability of the prediction by western blotting and real-time reverse transcription-quantitative polymerase chain reaction (RT-qPCR). ELISAs kit were used to measure changes in levels of proinflammatory factors in rats with GA induced by MSU to demonstrate the efficacy of ARC in GA treatment.

Results: Forty-three chemical constituents in ARC were identified. ARC could regulate 65 targets through 29 active components, and then treat GA, which involved 1427 Gene Ontology (GO) terms and 146 signaling pathways. Signaling pathways such as proteoglycans in cancer, C-type lectin receptor signaling pathway, and TNF signaling pathway may have an important role in GA treatment with ARC. In silico results showed that the active components songoramine and ignavine had high binding to mitogen-activated protein kinase p38 alpha (MAPK14) and matrix metallopeptidase (MMP)9, indicating that ARC treatment of GA was through multiple components and multiple targets. In vitro experiments showed that AA in ARC could effectively reduce expression of MAPK14, MMP9, and cyclooxygenase2 (PTGS2) in THP-1 cells stimulated by MSU, whereas it could significantly inhibit the mRNA expression of Caspase-1, spleen tyrosine kinase (SYK), and PTGS2. Animal experiments showed that a ARC aqueous extract could significantly reduce expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and intereleukin (IL)-18 in the serum of GA rats stimulated by MSU. Hence, ARC may inhibit inflammation by regulating the proteoglycans in cancer-associated signaling pathways.

Conclusion: ARC treatment of GA may have the following mechanisms, ARC can reduce MSU crystal-induced joint swelling, reduce synovial tissue damage, and reduce the expression of inflammatory factors in serum. AA in ARC may inhibit inflammation by regulating the protein expression of MAPK14, MMP9, and PTGS2 and the mRNA expression of caspase-1, SYK, and PTGS2.

• aconiti radix cocta
• active ingredients
• gouty arthritis
• mechanism of action
• systems pharmacology

• Colchicine
• Corticosteroids
• Gout
• Gout flare
• Interleukin 1 inhibitors
• Non-steroidal anti-inflammatory
• Treatment

Interleukin-1 (IL-1) plays a key role in the pathogenesis of different rheumatic diseases. There are now several agents available on the market capable of blocking IL-1. The proven effectiveness and excellent safety of these drugs makes them a possible therapeutic option in the treatment of IL-1 driven diseases, when previous therapies are contraindicated or ineffective. This article discusses the European wide off-label use of these drugs for the treatment of rheumatic diseases.

• anakinra
• anti IL-1
• canakinumab
• off-label use
• rheumatic diseases

Polygenic autoinflammatory diseases (AIDs), such as systemic juvenile idiopathic arthritis (sJIA), adult-onset Still's disease, Kawasaki disease, idiopathic recurrent pericarditis (IRP), Behçet’s Syndrome, Crystal-induced arthropatihes such as gout or Calcium pyrophosphate deposition disease are characterized by the overexpression of inflammasome-associated genes, leading to a dysregulation of the innate immune response. The IL-1 cytokine family (IL-1α, IL-1β, IL-1Ra, IL-18, IL-36Ra, IL-36α, IL-37, IL-36β, IL-36g, IL-38, IL-33) was defined to be principally responsible for the inflammatory nature of polygenic AIDs. Several clinical trials were initiated, and IL-1 blockade has been proven to cause a rapid reduction of clinical symptoms and normalization of laboratory parameters in the majority of cases. Randomized, placebo-controlled, clinical trials, together with registry-based clinical trials and open-label, retrospective and prospective observational studies, supported the efficacy and safety of IL-1 inhibitors in the treatment of polygenic AIDs. Most of the current data are focused on the therapeutic use of anakinra, an IL-1 receptor antagonist, canakinumab, an anti-IL-1β monoclonal antibody, and rilonacept, a soluble decoy receptor. However, other promising agents, such as gevokizumab, IL-1β blocking monoclonal antibody, tadekinig alfa, a human recombinant IL-18-binding protein, and tranilast, an analog of a tryptophan metabolite, are currently being tested. Anakinra, canakinumab and rilonacept caused impressive improvements in both systemic and musculoskeletal symptoms. Furthermore, the anti-IL-1 therapy allowed corticosteroid tapering and, in some cases, even withdrawal. This article reviews the current IL-1 inhibitors and the results of all clinical trials in which they have been tested for the management of broad spectrum of polygenic AIDs.

• IL-1
• adult-onset Still´s disease
• anakinra
• canakinumab
• idiopathic recurrent pericarditis
• rilonacept
• systemic juvenile idiopathic arthritis

• immune response
• inflammasome
• nucleotide-binding and oligomerization domain-like receptors and pyrin domain containing receptor 3
• pneumococcus (Streptococcus pneumoniae)
• respiratory infection

• Animals
• Arthritis, Rheumatoid/drug therapy
• Arthritis, Rheumatoid/immunology
• Arthritis, Rheumatoid/metabolism
• Autoimmune Diseases/drug therapy
• Autoimmune Diseases/immunology
• Autoimmune Diseases/metabolism
• Caspase 1/metabolism
• Cytokines/antagonists & inhibitors
• Cytokines/metabolism
• Diabetes Mellitus, Type 2/drug therapy
• Diabetes Mellitus, Type 2/immunology
• Diabetes Mellitus, Type 2/metabolism
• Humans
• Immunosuppressive Agents/adverse effects
• Immunosuppressive Agents/pharmacology
• Immunosuppressive Agents/therapeutic use
• Inflammasomes/antagonists & inhibitors
• Inflammasomes/immunology
• Inflammasomes/metabolism
• Inflammation/metabolism
• Interleukin-1beta/antagonists & inhibitors
• Interleukin-1beta/metabolism
• NLR Family, Pyrin Domain-Containing 3 Protein/genetics
• NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
• Osteoarthritis/drug therapy
• Osteoarthritis/immunology
• Osteoarthritis/metabolism
• Pneumococcal Infections/immunology
• Pneumococcal Infections/metabolism
• Respiratory Tract Infections/immunology
• Respiratory Tract Infections/metabolism
• Respiratory Tract Infections/microbiology

Inflammasomes are macromolecular complexes formed in response to pathogen‐associated molecular patterns (PAMPs) and danger‐associated molecular patterns (DAMPs) that drive maturation of the pro‐inflammatory cytokines interleukin (IL)‐1β and IL‐18, and cleave gasdermin D (GSDMD) for induction of pyroptosis. Inflammasomes are highly important in protecting the host from various microbial pathogens and sterile insults. Inflammasome pathways are strictly regulated at both transcriptional and post‐translational checkpoints. When these checkpoints are not properly imposed, undue inflammasome activation may promote inflammatory, metabolic and oncogenic processes that give rise to autoinflammatory, autoimmune, metabolic and malignant diseases. In addition to clinically approved IL‐1‐targeted biologics, upstream targeting of inflammasome pathways recently gained interest as a novel pharmacological strategy for selectively modulating inflammasome activation in pathological conditions.

• GSDMD
• IL-1
• NLRP3
• disease
• immunotherapy
• inflammasome
• inflammation
• pyroptosis

Inflammation is involved in tumor development and progression as well as antitumor response to therapy. In the past decade, the crosstalk between inflammation, immunity, and cancer has been investigated extensively, which led to the identification of several underlying mechanisms and cells involved. The formation of inflammasome complexes leads to the activation of caspase-1, production of interleukin (IL)-1β, and IL-18 and pyroptosis. Multiple studies have shown the involvement of NLRP3 inflammasome in tumorigenesis. Conversely, other reports have indicated a protective role in certain cancers. In this review, we summarize these contradictory roles of NLRP3 inflammasome in cancer, shed the light on oncogenic signaling leading to NLRP3 activation and IL-1β production and outline the current knowledge on therapeutic approaches.

• NLRP3
• activation
• cancer
• inflammasome
• therapeutic targets

• Colchicine
• Corticosteroids
• Gout
• Gout flare
• IL-1 inhibitors
• NSAIDs

• Anti-Inflammatory Agents, Non-Steroidal/therapeutic use
• Colchicine/therapeutic use
• Gout/diagnosis
• Gout/drug therapy
• Gout/epidemiology
• Gout Suppressants/therapeutic use
• Humans
• Rheumatology

• Anakinra
• Canakinumab
• Dupilumab
• Mepolizumab
• Rilonacept
• Sarilumab
• Siltuximab
• Tocilizumab

Inflammasomes are multimeric complexes composed of cytoplasmic sensors, apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC or PYCARD), and procaspase-1 and play roles in regulating caspase-dependent inflammation and cell death. Inflammasomes are assembled by sensing pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) and initiate inflammatory responses by activating caspase-1. Activated caspase-1 promotes the release of the inflammatory cytokines interleukin-1β (IL-1β) and IL-18 and eventually induces pyroptosis. Inflammasomes are closely related to kidney diseases. In particular, the NLRP3 (NACHT, LRR, and PYD domain-containing protein 3) inflammasome has been shown to cause acute and chronic kidney diseases by regulating canonical and noncanonical mechanisms of inflammation. Small-molecule inhibitors that target NLRP3 and other components of the inflammasome are potential options for the treatment of kidney-related diseases such as diabetic nephropathy. This article will focus on the research progress on inflammasomes and the key pathogenic roles of inflammasomes in the development and progression of kidney diseases and explore the potential of this intracellular inflammation to further prevent or block the development of the kidney disease.

The interleukin-1 (IL-1) receptor antagonist anakinra is an effective, off-label option in acute gout flares, when conventional therapy options are narrowed. We performed a retrospective, randomized, case-controlled study to gain clinical insight on baseline factors for gout patients most likely to receive anakinra, and ultimate mortality of those who received anakinra.

Of 1451 gout patients seen between January 2003 and January 2015 in a Veterans Affairs (VA) rheumatology group practice, under stringent managed care principles, 13 (100% male), who received anakinra at least once for flares, were compared with 1:4 age- and sex-matched gout controls. Each patient’s first rheumatology encounter was studied by factor analysis for variables associated with later anakinra.

At baseline, patients that received anakinra had higher urate burden (palpable tophi [10/13] vs controls [16/52], P = .003), serum urate ([10.6 mg/dL] vs controls [7.6 mg/dL], P < .0001), and East Asian descent ([7/13] vs [16/52], P = .041). The anakinra group had higher ultimate all-cause mortality ([6/13] vs controls [7/52], relative risk [RR] = 3.43, 95% confidence interval [CI] = 1.39-8.48, P = .0076). Factor analysis showed baseline visit palpable tophus and statin use to be most strongly associated with later anakinra use. Increased mortality of anakinra users, as per a factorial analysis, was linked more strongly to comorbidities than to anakinra.

At baseline rheumatology gout encounter, higher urate, palpable tophi, statin prescription, and East Asian descent were associated with later anakinra use for flares. Mortality was more closely associated to the presence of comorbidities at baseline rheumatology visit than to anakinra prescription.

• Gout
• arthritis
• cytokines
• hyperuricemia
• mortality

• Autoimmunity
• Caspase-1
• Inflammasome
• Interleukin-1β

• ANAKINRA
• CALCIUM PYROPHOSPHATE
• CRYSTAL-ASSOCIATED ARTHRITIS
• GOUT
• PSEUDOGOUT

• ANAKINRA
• GOUT
• PSEUDOGOUT

Gout is an inflammatory arthritis caused by monosodium urate monohydrate (MSU) crystals’ joint deposition. MSU phagocytosis by resident macrophages is a key step in gout pathogenesis. MSU phagocytosis triggers nuclear factor kappa B (NFκB) activation and production of cytokines and chemokines. Proteoglycan-4 (PRG4) is a glycoprotein produced by synovial fibroblasts and exerts an anti-inflammatory effect in the joint mediated by its interaction with cell surface receptor CD44. PRG4 also binds and antagonizes TLR2 and TLR4. The objective of this study is to evaluate the efficacy of recombinant human PRG4 (rhPRG4) in suppressing MSU-induced inflammation and mechanical allodynia in vitro and in vivo.

THP-1 macrophages were incubated with MSU crystals ± rhPRG4 or bovine submaxillary mucin (BSM), and crystal phagocytosis, cytokines and chemokines expression and production were determined. NFκB p65 subunit nuclear translocation, NLRP3 induction, caspase-1 activation and conversion of proIL-1β to mature IL-1β were studied. MSU phagocytosis by Prg4^+/+ and Prg4^−/− peritoneal macrophages was determined in the absence or presence of rhPRG4, BSM, anti-CD44, anti-TLR2, anti-TLR4 and isotype control antibodies. Rhodamine-labeled rhPRG4 was incubated with murine macrophages and receptor colocalization studies were performed. Lewis rats underwent intra-articular injection of MSU crystals followed by intra-articular treatment with PBS or rhPRG4. Weight bearing and SF myeloperoxidase activities were determined.

rhPRG4 reduced MSU crystal phagocytosis at 4 h (p < 0.01) and IL-1β, TNF-α, IL-8 and MCP-1 expression and production at 6 h (p < 0.05). BSM did not alter MSU phagocytosis or IL-1β production in human and murine macrophages. rhPRG4 treatment reduced NFκB nuclear translocation, NLRP3 expression, caspase-1 activation and generation of mature IL-1β (p < 0.05). MSU-stimulated IL-1β production was higher in Prg4^−/− macrophages compared to Prg4^+/+ macrophages (p < 0.001). rhPRG4, anti-CD44, anti-TLR2 and anti-TLR4 antibody treatments reduced MSU phagocytosis and IL-1β production in murine macrophages (p < 0.05). rhPRG4 preferentially colocalized with CD44 on Prg4^−/− peritoneal macrophages compared to TLR2 or TLR4 (p < 0.01). rhPRG4 normalized weight bearing and reduced SF myeloperoxidase activity compared to PBS in vivo.

rhPRG4 inhibits MSU crystal phagocytosis and exhibits an anti-inflammatory and anti-nociceptive activity in vitro and in vivo. rhPRG4’s anti-inflammatory mechanism may be due to targeting CD44 on macrophages.

• CD44
• Gout
• Lubricin
• Macrophages
• Proteoglycan-4
• TLR2
• TLR4
• Urate