Inflammation-related Cells Research Articles

NMDAR Down-Regulation: Dual - Hit Molecular Target For COPD - Depression Comorbidity.

Chronic obstructive pulmonary disease (COPD) is a chronic lung disease characterized by sustained airflow limitation that represents one of the main causes of disability in modern society. Depression affects approximately 40% of COPD patients. Both COPD and depression are associated with chronic systemic inflammation and their comorbidity represents a critical unmet treatment need. N-methyl-D-aspartate glutamatergic receptors (NMDAR) are well characterized in the central nervous system (CNS) and widely expressed in lung tissue and inflammation-related cells. Accumulating evidence indicates that pathologic NMDAR up-regulation, leading to pro-inflammatory pathways activation and tissue damage, may play a crucial role in chronic lung injury as well as in depression. D-cycloserine, a bacteriostatic antibiotic used since the 1950's in tuberculosis, acts at therapeutic dosages also as a NMDAR functional antagonist and has antidepressant and anti-inflammatory effects. We hypothesize that NMDAR down-regulation may represent a unified molecular target for the treatment of COPD - depression comorbidity and may simultaneously alleviate both respiratory and depression symptomatology. We postulate that D-cycloserine treatment may achieve these dual - hit objectives and envisage that our hypotheses may apply to additional inflammation disorders that are frequently accompanied by depression.

Inflammatory stimulus-responsive polymersomes reprogramming glucose metabolism mitigates rheumatoid arthritis

Inflammation-resident cells within arthritic sites undergo a metabolic shift towards glycolysis, which greatly aggravates rheumatoid arthritis (RA). Reprogramming glucose metabolism can suppress abnormal proliferation and activation of inflammation-related cells without affecting normal cells, holding potential for RA therapy. Single 2-deoxy-d-glucose (2-DG, glycolysis inhibitor) treatment often cause elevated ROS, which is detrimental to RA remission. The rational combination of glycolysis inhibition with anti-inflammatory intervention might cooperatively achieve favorable RA therapy. To improve drug bioavailability and exert synergetic effect, stable co-encapsulation of drugs in long circulation and timely drug release in inflamed milieu is highly desirable. Herein, we designed a stimulus-responsive hyaluronic acid-triglycerol monostearate polymersomes (HTDD) co-delivering 2-DG and dexamethasone (Dex) to arthritic sites. After intravenous injection, HTDD polymersomes facilitated prolonged circulation and preferential distribution in inflamed sites, where overexpressed matrix metalloproteinases and acidic pH triggered drug release. Results indicated 2-DG can inhibit the excessive cell proliferation and activation, and improve Dex bioavailability by reducing Dex efflux. Dex can suppress inflammatory signaling and prevent 2-DG-induced oxidative stress. Thus, the combinational strategy ultimately mitigated RA by inhibiting glycolysis and hindering inflammatory signaling. Our study demonstrated the great potential in RA therapy by reprogramming glucose metabolism in arthritic sites.

Predicting Flare in Patients With Rheumatoid Arthritis in Biologic Induced Remission, on Tapering, and on Stable Therapy.

The tapering of biologic disease-modifying antirheumatic drug (b-DMARD) therapy for patients with rheumatoid arthritis (RA) in stable remission is frequently undertaken, but specific guidance on how to successfully taper is lacking. The objective of this study is to identify predictors of flare in patients in stable b-DMARD-induced clinical remission, who did or did not follow structured b-DMARD tapering. Patients with RA receiving b-DMARD treatment who had achieved sustained remission according to a Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP) <2.6 for ≥6 months were offered tapering. Clinical, ultrasound (US) (total power Doppler [PD]/grayscale abnormalities), CD4+ T cell subsets, and patient-reported outcomes (PROs) were collected at inclusion. The primary endpoint was the occurrence of flare (loss of DAS28-CRP remission) over 12 months. Logistic regression analyses identified predictors of flare. Dichotomization into high/low-risk groups was based on 80% specificity using the area under the receiving operator curve (AUROC). Of 63 patients choosing tapering, 23 (37%) flared compared with 12 of 60 (20%) on stable treatment (P = 0.043). All patients who flared regained remission upon reinstating treatment. In the tapering group, flare was associated with lower regulatory T cell (Treg) (P < 0.0001) and higher CRP levels (P < 0.0001), erythrocyte sedimentation rate (P < 0.035), and inflammation-related cells (IRCs) (P = 0.054); stepwise modeling selected Tregs (odds ratio [OR] = 0.350, P = 0.004), IRCs (OR=1.871, P = 0.007), and CRP level (OR=1.577, P = 0.004) with 81.7% accuracy and AUROC=0.890. In the continued therapy group, modeling retained the tender joint count, total PD, and visual analog scale pain score, with 82.1% accuracy and AUROC=0.899. Most patients in the study were considered low risk of flare (80 of 123 patients [65%]). Only 5 of 37 (13.5%) of the low-risk patients who tapered flared, which was notable compared with the continued therapy group (20% flare). Flare on tapering b-DMARDs was predicted by lower Tregs and elevated inflammation biomarkers (IRCs/CRP level); flare on continued b-DMARDs was associated with raised pain parameters and US inflammation. Knowledge of these biomarkers should improve outcomes by targeted selection for tapering, and by increased monitoring of those on continued therapy predicted to flare.

Lymphocyte subset phenotyping for the prediction of progression to inflammatory arthritis in anti-citrullinated-peptide antibody-positive at-risk individuals.

Inflammatory arthritis (IA) is considered the last stage of a disease continuum, where features of systemic autoimmunity can appear years before clinical synovitis. Time to progression to IA varies considerably between at-risk individuals, therefore the identification of biomarkers predictive of progression is of major importance. We previously reported on the value of three CD4+T cell subsets as biomarkers of progression. Here, we aim to establish the value of 18 lymphocyte subsets (LS) for predicting progression to IA. Participants were recruited based on a new musculoskeletal complaint and being positive for anti-citrullinated-peptide antibody. Progression (over 10 years) was defined as the development of clinical synovitis. LS analysis was performed for lymphocyte lineages, naive/memory subsets, inflammation-related cells (IRC) and regulatory cells (Treg/B-reg). Modelling used logistic/Cox regressions. Of 210 patients included, 93 (44%) progressed to IA, 41/93 (44%) within 12 months (rapid progressors). A total of 5/18 LS were associated with progression [Treg/CD4-naïve/IRC (adjusted P < 0.0001), CD8 (P = 0.021), B-reg (P = 0.015)] and three trends (NK-cells/memory-B-cells/plasmablasts). Unsupervised hierarchical clustering using these eight subsets segregated three clusters of patients, one cluster being enriched [63/109(58%)] and one poor [10/45(22%)] in progressors. Combining all clinical and LS variables, forward logistic regression predicted progression with accuracy = 85.7% and AUC = 0.911, selecting smoking/rheumatoid-factor/HLA-shared-epitope/tender-joint-count-78 and Treg/CD4-naive/CD8/NK-cells/B-reg/plasmablasts. To predict rapid progression, a Cox regression was performed resulting in a model combining smoking/rheumatoid factor and IRC/CD4-naive/Treg/NK-cells/CD8+T cells (AUC = 0.794). Overall, progression was predicted by specific LS, suggesting potential triggers for events leading to the development of IA, while rapid progression was associated with a different set of subsets.

A novel UV-curable extravascular stent to prevent restenosis of venous grafts

The incidence of coronary heart disease is increasing yearly. Coronary artery bypass graft (CABG) is an important surgical method for the treatment of coronary heart disease. The vein grafts in CABG surgery mostly use saphenous vein, but restenosis of the graft frequently occurs, and has become an urgent clinical problem. In this study, we produced a UV-curable Hydroxyethyl Methacrylate (HEMA) gel containing Bletilla striata , and compared its tensile strength and expansibility to that of human vessels, showing that the film has good physical properties. Through cell experiments, we proved that film has no effect on cell proliferation, migration, apoptosis, and DNA damage. In addition, we placed the film under the skin of mice to measure inflammation-related cells and factors, and found that it did not trigger the body's immune response. After that, we designed a rat vein graft model to simulate the pathological changes of the vein graft vessel after CABG. The film had a good inhibitory effect on the restenosis of vein graft vessels in the rat model. Finally, analysis of the expression levels of proteins involved in the proliferation and migration indicated that the gel can effectively inhibit these processes in smooth muscle cells in the graft vein. In conclusion, this study has successfully produced a UV-curable HEMA gel containing B. striata that could effectively inhibit the restenosis of vein grafts. Fig Abstract: a: In CABG, the saphenous vein is removed and grafted onto the coronary arteries of the heart. b：The gelatinous scaffold is wrapped around the vessel while in liquid state. After UV curing, the scaffold can provide support for the vein graft. • The extravascular stents can be cured under UV light. • The extravascular stent can encapsulate Bletilla striata polysaccharide and release it stably. • The extravascular stents can effectively inhibit vascular restenosis. • The extravascular stent has good histocompatibility and cytocompatibility.

Polymer Nanomedicines with Ph-Sensitive Release of Dexamethasone for the Localized Treatment of Inflammation

Polymer-drug conjugates have several advantages in controlled drug delivery to inflammation as they can accumulate and release the drug in inflamed tissues or cells, which could circumvent the shortcomings of current therapy. To improve the therapeutic potential of polymer-drug conjugates in joint inflammation, we synthesized polymer conjugates based on N-(2-hydroxypropyl) methacrylamide) copolymers labeled with a near-infrared fluorescent dye and covalently linked to the anti-inflammatory drug dexamethasone (DEX). The drug was bound to the polymer via a spacer enabling pH-sensitive drug release in conditions mimicking the environment inside inflammation-related cells. An in vivo murine model of adjuvant-induced arthritis was used to confirm the accumulation of polymer conjugates in arthritic joints, which occurred rapidly after conjugate application and remained until the end of the experiment. Several tested dosage schemes of polymer DEX-OPB conjugate showed superior anti-inflammatory efficacy. The highest therapeutic effect was obtained by repeated i.p. application of polymer conjugate (3 × 1 mg/kg of DEX eq.), which led to a reduction in the severity of inflammation in the ankle by more than 90%, compared to 40% in mice treated with free DEX.

T cell subsets: an immunological biomarker to predict progression to clinical arthritis in ACPA-positive individuals.

ObjectivesAnticitrullinated protein antibody (ACPA)+ individuals with non-specific musculoskeletal symptoms are at risk of inflammatory arthritis (IA). This study aims to demonstrate the predictive value of T cell subset quantification for progression towards IA and compare it with previously identified clinical predictors of progression.Methods103 ACPA+ individuals without clinical synovitis were observed 3-monthly for 12 months and then as clinically indicated. The end point was the development of IA. Naïve, regulatory T cells (Treg) and inflammation related cells (IRCs) were quantified by flow cytometry. Areas under the ROC curve (AUC) were calculated. Adjusted logistic regressions and Cox proportional hazards models for time to progression to IA were constructed.ResultsCompared with healthy controls (age adjusted where appropriate), ACPA+ individuals demonstrated reduced naïve (22.1% of subjects) and Treg (35.8%) frequencies and elevated IRC (29.5%). Of the 103 subjects, 48(46.6%) progressed. Individually, T cell subsets were weakly predictive (AUC between 0.63 and 0.66), although the presence of 2 T cell abnormalities had high specificity. Three models were compared: model-1 used T cell subsets only, model-2 used previously published clinical parameters, model-3 combined clinical data and T cell data. Model-3 performed the best (AUC 0.79 (95% CI 0.70 to 0.89)) compared with model-1 (0.75 (0.65 to 0.86)) and particularly with model-2 (0.62 (0.54 to 0.76)) demonstrating the added value of T cell subsets. Time to progression differed significantly between high-risk, moderate-risk and low-risk groups from model-3 (p=0.001, median 15.4 months, 25.8 months and 63.4 months, respectively).ConclusionsT cell subset dysregulation in ACPA+ individuals predates the onset of IA, predicts the risk and faster progression to IA, with added value over previously published clinical predictors of progression.

Alleviation of capsular formations on silicone implants in rats using biomembrane-mimicking coatings

Despite their popular use in breast augmentation and reconstruction surgeries, the limited biocompatibility of silicone implants can induce severe side effects, including capsular contracture – an excessive foreign body reaction that forms a tight and hard fibrous capsule around the implant. This study examines the effects of using biomembrane-mimicking surface coatings to prevent capsular formations on silicone implants. The covalently attached biomembrane-mimicking polymer, poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC), prevented nonspecific protein adsorption and fibroblast adhesion on the silicone surface. More importantly, in vivo capsule formations around PMPC-grafted silicone implants in rats were significantly thinner and exhibited lower collagen densities and more regular collagen alignments than bare silicone implants. The observed decrease in α-smooth muscle actin also supported the alleviation of capsular formations by the biomembrane-mimicking coating. Decreases in inflammation-related cells, myeloperoxidase and transforming growth factor-β resulted in reduced inflammation in the capsular tissue. The biomembrane-mimicking coatings used on these silicone implants demonstrate great potential for preventing capsular contracture and developing biocompatible materials for various biomedical applications.

A1.33 Predicting the evolution of inflammatory arthritis in ACPA-positive individuals: can T-cell subsets help?

Background and ObjectivesACPA+ individuals with non-specific musculoskeletal symptoms are at high risk of developing rheumatoid arthritis (RA). We previously demonstrated dys-regulation of T-cell subsets with loss of naïve and regulatory...

An immunological biomarker to predict MTX response in early RA

ObjectivesThe therapeutic goal for patients with rheumatoid arthritis (RA) is clinical remission. This is best achieved by early diagnosis and appropriate therapeutic intervention. RA is associated with dysregulation of T-cell...

THU0032 Predicting the Evolution of Inflammatory Arthritis in ACPA-Positive Individuals: can T-Cell Subset Help?

BackgroundACPA+ individuals with non specific musculoskeletal symptoms are at high risk of developing rheumatoid arthritis (RA). We previously demonstrated dys-regulation of T-cell subsets with loss of naïve and regulatory T-cell...

Predicting the evolution of inflammatory arthritis in ACPA-positive individuals: can T cell subset help?

Backgroundand objectivesAnticitrullinated protein antibodies (ACPA)+ individuals with musculoskeletal pain are at high risk of developing rheumatoid arthritis (RA). The authors previously demonstrated dys-regulation of T cell subsets in early disease...

Ultraviolet B radiation and reactive oxygen species modulate interleukin-31 expression in T lymphocytes, monocytes and dendritic cells

Interleukin (IL)-31 is a novel Th2 T-cell cytokine that induces pruritus and dermatitis in transgenic mice. While enhanced mRNA expression of this cytokine is detected in skin samples of inflammatory skin diseases, the regulation of IL-31 expression is poorly understood. To assess the effects of ultraviolet (UV) B radiation and H₂O₂ on IL-31 mRNA and protein expression in skin and different peripheral blood mononuclear cells (PBMCs). The effects of UVB radiation and H₂O₂, as a prototypic reactive oxygen species, on IL-31 mRNA and protein expression were analysed in various inflammation-related cells and murine skin tissue. RESULTSTreatment of cells with UVB radiation and H₂ O₂ strongly induced IL-31 mRNA and protein expression in human PBMCs and in the skin of SKH-1 mice. Following exposure to UVB or H₂O₂, we observed increased expression of IL-31 mRNA in T cells, monocytes, macrophages, and immature and especially mature dendritic cells. H₂O₂ treatment but not UVB radiation led to a moderate upregulation of IL-31 mRNA expression in epidermal keratinocytes and dermal fibroblasts. Pretreatment of T lymphocytes with the MAPK p38 inhibitor SB203580 or the MEK1 inhibitor U0126 reduced the stimulatory effect of H₂O₂. These experiments suggest that p38 is involved in the regulation of IL-31 expression in human skin. Our studies reveal that UVB and reactive oxygen species stimulate the expression of IL-31 in PBMCs and skin, especially in T cells, monocytes and monocyte-derived dendritic cells.

Severity of T cell subset dysregulation influences the probability of achieving drug-induced remission in early arthritis

The authors reported that immunological parameters can predict the response to treatment in early rheumatoid arthritis independently of the treatment received as well as relapse in patients who achieved clinical...

Abnormal T cell differentiation persists in patients with rheumatoid arthritis in clinical remission and predicts relapse

Objectives:An abnormal CD4+ T cell subset related to inflammation exposure (inflammation-related cells, IRC) has been identified in rheumatoid arthritis (RA). Patients with inflammatory and non-inflammatory diseases were used to examine...