Metabolic Checkpoints in Rheumatoid Arthritis

Several studies have highlighted the interplay between metabolism, immunity and inflammation. Both tissue resident and infiltrating immune cells play a major role in the inflammatory process of rheumatoid arthritis (RA) via the production of cytokines, adipo-cytokines and metabolic intermediates. These functions are metabolically demanding and require the most efficient use of bioenergetic pathways. The synovial membrane is the primary site of inflammation in RA and exhibits distinctive histological patterns characterized by different metabolism, prognosis and response to treatment. In the RA synovium, the high energy demand by stromal and infiltrating immune cells, causes the accumulation of metabolites, and adipo-cytokines, which carry out signaling functions, as well as activating transcription factors which act as metabolic sensors. These events drive immune and joint-resident cells to acquire pro-inflammatory effector functions which in turn perpetuate chronic inflammation. Whether metabolic changes are a consequence of the disease or one of the causes of RA pathogenesis is still under investigation. This review covers our current knowledge of cell metabolism in RA. Understanding the intricate interactions between metabolic pathways and the inflammatory and immune responses will provide more awareness of the mechanisms underlying RA pathogenesis and will identify novel therapeutic options to treat this disease

Neonatal-onset multisystem inflammatory disease responsive to interleukin-1 beta inhibition

BACKGROUND:Neonatal-onset multisystem inflammatory disease is characterized by fever, urticarial rash, aseptic meningitis, deforming arthropathy, hearing loss, and mental retardation. Many patients have mutations in the cold-induced autoinflammatory syndrome 1 (CIAS1) gene, encoding cryopyrin, a protein that regulates inflammation.METHODS:We selected 18 patients with neonatal-onset multisystem inflammatory disease (12 with identifiable CIAS1 mutations) to receive anakinra, an interleukin-1-receptor antagonist (1 to 2 mg per kilogram of body weight per day subcutaneously). In 11 patients, anakinra was withdrawn at three months until a flare occurred. The primary end points included changes in scores in a daily diary of symptoms, serum levels of amyloid A and C-reactive protein, and the erythrocyte sedimentation rate from baseline to month 3 and from month 3 until a disease flare.RESULTS:All 18 patients had a rapid response to anakinra, with disappearance of rash. Diary scores improved (P<0.001) and serum amyloid A (from a median of 174 mg to 8 mg per liter), C-reactive protein (from a median of 5.29 mg to 0.34 mg per deciliter), and the erythrocyte sedimentation rate decreased at month 3 (all P<0.001), and remained low at month 6. Magnetic resonance imaging showed improvement in cochlear and leptomeningeal lesions as compared with baseline. Withdrawal of anakinra uniformly resulted in relapse within days; retreatment led to rapid improvement. There were no drug-related serious adverse events.CONCLUSIONS:Daily injections of anakinra markedly improved clinical and laboratory manifestations in patients with neonatal-onset multisystem inflammatory disease, with or without CIAS1 mutations

Insulin signaling in arthritis

Inflammatory arthritis is burdened by an increased risk of metabolic disorders. Cytokines and other mediators in inflammatory diseases lead to insulin resistance, diabetes and hyperlipidemia. Accumulating evidence in the field of immunometabolism suggests that the cause-effect relationship between arthritis and metabolic abnormalities might be bidirectional. Indeed, the immune response can be modulated by various factors such as environmental agents, bacterial products and hormones. Insulin is produced by pancreatic cells and regulates glucose, fat metabolism and cell growth. The action of insulin is mediated through the insulin receptor (IR), localized on the cellular membrane of hepatocytes, myocytes and adipocytes but also on the surface of T cells, macrophages, and dendritic cells. In murine models, the absence of IR in T-cells coincided with reduced cytokine production, proliferation, and migration. In macrophages, defective insulin signaling resulted in enhanced glycolysis affecting the responses to pathogens. In this review, we focalize on the bidirectional cause-effect relationship between impaired insulin signaling and arthritis analyzing how insulin signaling may be involved in the aberrant immune response implicated in arthritis and how inflammatory mediators affect insulin signaling. Finally, the effect of glucose-lowering agents on arthritis was summarized.Pathophysiology and treatment of rheumatic disease

Lactate Buildup at the Site of Chronic Inflammation Promotes Disease by Inducing CD4(+) T Cell Metabolic Rewiring

Accumulation of lactate in the tissue microenvironment is a feature of both inflammatory disease and cancer. Here, we assess the response of immune cells to lactate in the context of chronic inflammation. We report that lactate accumulation in the inflamed tissue contributes to the upregulation of the lactate transporter SLC5A12 by human CD4+ T&nbsp;cells. SLC5A12-mediated lactate uptake into CD4+ T&nbsp;cells induces a reshaping of their effector phenotype, resulting in increased IL17 production via nuclear PKM2/STAT3 and enhanced fatty acid synthesis. It also leads to CD4+ T&nbsp;cell retention in the inflamed tissue as a consequence of reduced glycolysis and enhanced fatty acid synthesis. Furthermore, antibody-mediated blockade of SLC5A12 ameliorates the disease severity in a murine model of arthritis. Finally, we propose that lactate/SLC5A12-induced metabolic reprogramming is a distinctive feature of lymphoid synovitis in rheumatoid arthritis patients and a potential therapeutic target in chronic inflammatory disorders

Coordination complexes of NbX5 (X = F, Cl) with (N,O)- and (O,O)-donor ligands and the first X-ray characterization of a neutral NbF5 adduct

A variety of fairly air-stable complexes were prepared by straightforward reactions of NbX5 (X = F, Cl) with a series of potential bidentate (N,O)- and (O,O)-donor ligands in CH2Cl2. NbF5reacted with equi-molar amounts of 2-[(2,6-diisopropylphenyl)iminomethyl]phenol (dpimpH) and 2-benzoyl-6-hydroxy-6-phenylpentafulvene (bhpfH) to afford the mononuclear complexes NbF5[κ1(O)-OC6H4CHNHC6H3(CHMe2)2], 2, and NbF5[κ1(O)-bhpfH], 7, respectively. The 1 : 1 reactions of NbF5 with salicylaldehyde oxime (saoH2) and 2-phenylaminoethanol gave the hexafluoroniobato salts [NbF4{κ1(O)-ON(H)CHC6H4OH}2][NbF6], 3, and [NbF4{κ1(O)-OCH2CH2NH2Ph}2][NbF6], 6, respectively. The syntheses of 2, 3 and 6 are accompanied by oxygen to nitrogen intramolecular H migration, leading to the formation of metal–alkoxide moieties. The parallel chemistry of NbCl5 is characterised by HCl release. The 1 : 1 reactions with dpimpH, saoH2 and bhpfH yielded, respectively, the ionic complex [NbCl2{κ1(N):κ1(O)-dpimp}2][NbCl6], 4a, the neutral-dinuclear Nb2Cl7[κ1(O)-saoH][κ2(O)-sao], 5, and the mononuclear NbCl4[κ2(O)-bhpf ],8. The tantalum species [TaCl2{κ1(N):κ1(O)-dpimp}2][TaCl6], 4b, was prepared from TaCl5/dpimpH. The new products 2–8 were fully characterized by analytical and spectroscopic techniques. Moreover the solid state structures of 2 and 8 were ascertained by X-ray diffraction studies; the structure of 2 exhibits an intramolecular bifurcated N–H⋯(O,F) hydrogen bond. DFT calculations were carried out in order to predict the lowest energy structures in the distinct cases, showing generally good agreement with the experimental data

The N-Formyl Peptide Receptors and Rheumatoid Arthritis: A Dangerous Liaison or Confusing Relationship?

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by a progressive symmetric inflammation of the joints resulting in bone erosion and cartilage destruction with a progressive loss of function and joint deformity. An increased number of findings support the role of innate immunity in RA: many innate immune mechanisms are responsible for producing several cytokines and chemokines involved in RA pathogenesis, such as Tumor Necrosis Factor (TNF)-α, interleukin (IL)-6, and IL-1. Pattern recognition receptors (PRRs) play a crucial role in modulating the activity of the innate arm of the immune response. We focused our attention over the years on the expression and functions of a specific class of PRR, namely formyl peptide receptors (FPRs), which exert a key function in both sustaining and resolving the inflammatory response, depending on the context and/or the agonist. We performed a broad review of the data available in the literature on the role of FPRs and their ligands in RA. Furthermore, we queried a publicly available database collecting data from 90 RA patients with different clinic features to evaluate the possible association between FPRs and clinic-pathologic parameters of RA patients

Drug use and abuse and the risk of adverse events in soccer players: results from a survey in Italian second league players

Objectives.Drug use in athletes has been frequently investigated in the last three decades, especially regarding its misuse for doping. However little is known about the use of permitted drugs for medical purposes and less studies have investigated the relationship between adverse drugs reactions (ADRs) and sports. Methods.An observational cross-sectional investigation analyzing a group of second league soccer players (the second-highest division in Italy) was performed. Anamnestic and physical examinations as well as a validated questionnaire (AQUA©) were performed in a group of 378 Italian second league soccer players. Results.Most players (91.8%) reported the use of NSAIDs in the previous year, and one third of them were regular users. Analgesics were used in 64% of the players, while 52.1% had taken antibiotics in the previous year. 29.20% of players used intraarticular treatments in the previous year. In 7,4% of players, an ADRs was reported: 3,47% reacted to NSAIDs, 2,6% to antibiotics, 1,05% to analgesics and 1 of them to supplements. For intra-articular injections, only 2 players experienced ADRs. One quarter of players experienced reactions as urticaria-angioedema syndrome or more severe conditions as bronchospasm or anaphylaxys. Conclusions. This study shows that drug misuse/abuse in soccer is a real matter of debate, especially with regards to NSAIDs, exposing athletes to predictable and/or unpredictable risks for their health

Differential impact of high and low penetrance TNFRSF1A gene mutations on conventional and regulatory CD4+ T cell functions in TNFR1-associated periodic syndrome

TNFR-associated periodic syndrome is an autoinflammatory disorder caused by autosomal-dominantmutations in TNFRSF1A, the gene encoding for TNFR superfamily 1A. The lack of knowledge in the field of TNFR-associated periodic syndrome biology is clear, particularly in the context of control of immune self-tolerance. We investigated how TNF-\u3b1/TNFR superfamily 1A signaling can affect T cell biology, focusing on conventional CD4+CD25\uaf and regulatory CD4+CD25+ T cell functions in patients with TNFR-associated periodic syndrome carrying either high or low penetrance TNFRSF1A mutations. Specifically, we observed that in high penetrance TNFR-associated periodic syndrome, at the molecular level, these alterations were secondary to a hyperactivation of the ERK1/2, STAT1/3/5, mammalian target of rapamycin, and NF-kB pathways in conventional T cells. In addition, these patients had a lower frequency of peripheral regulatory T cells, which also displayed a defective suppressive phenotype. These alterations were partially found in low penetrance TNFR-associated periodic syndrome, suggesting a specific link between the penetrance of the TNFRSF1A mutation and the observed T cell phenotype. Taken together, our data envision a novel role for adaptive immunity in the pathogenesis of TNFR-associated periodic syndrome involving both CD4+ conventional T cells and Tregs, suggesting a novel mechanism of inflammation in the context of autoinflammatory disorders