scholarly journals Neuromedin U Suppresses Collagen-Induced Arthritis through ILC2-Th2 Activation

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Yuanyuan Zhang ◽  
Yi Qin ◽  
Zhu Chen
Keyword(s):  
Bone Erosion ◽  
Early Stage ◽  
Allergic Diseases ◽  
Th2 Cells ◽  
Collagen Induced Arthritis ◽  
Clinical Onset ◽  
Evolutionarily Conserved ◽  
Gata3 Expression ◽  
Underlying Mechanisms ◽  
Inflammatory Effect

Neuromedin U (NMU) is an evolutionarily conserved neuropeptide which was previously thought to have a proinflammatory property. Recently, it was reported that NMU induced rapid ILC2 activation and Th2 responses in allergic diseases. However, whether NMU could launch such responses in arthritis is not known. In this study, we investigated the effect of NMU administration on arthritis and its underlying mechanisms. C57BL/6 male mice were induced with collagen-induced arthritis (CIA) and treated with NMU-23 or PBS at an early stage of induction. NMU-23 dramatically inhibited clinical onset and severity of arthritis, accompanied with decreased bone erosion and number of osteoclasts. Mechanistically, NMU-23 administration induced the expansion of ILC2 and elevated eosinophil, IL-5, and IL-13 expression in the joint of arthritic mice. Although levels of Th2 cells are slightly increased, Gata3 expression level is also upregulated. Further, NMU-deficient (NMU-/-) mice develop less severe CIA compared with control. Interestingly, the proportion of ILC2 and FoxP3+ regulatory T cells (Treg) was elevated in NMU-/- mice. Taken together, our results reveal a previously unknown anti-inflammatory effect of NMU in CIA by inducing ILC2-Th2 activation.

scholarly journals SAT0025 NEUROMEDIN U SUPPRESSES COLLAGEN-INDUCED ARTHRITIS THROUGH ACTIVATION OF ILC2

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 942.2-942
Author(s):  
Y. Zhang ◽  
Y. Qin ◽  
Z. Chen
Keyword(s):  
Flow Cytometry ◽  
Molecular Mechanisms ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Th2 Cells ◽  
Repeated Injection ◽  
Collagen Induced Arthritis ◽  
Clinical Onset ◽  
Deficient Mice

Background:Reduction and dysregulation of ILC2 was linked to delayed resolution of arthritis. The neuropeptide Neuromedin U (NMU) has been reported to rapidly activate ILC2 and initiate a Th2 type immune response through NMUR1 expressed on the surface of ILC2. However, one previous study reported that NMU promoted autoantibody-mediated arthritis.Objectives:The aim of this work was to investigate the effect of NMU on collagen-induced arthritis (CIA) mice and the potential mechanisms.Methods:CIA was induced in C57BL/6 WT and C57BL/6Nmudeficient mice on day 1. WT mice were treated i.p. daily by NMU-23 (20ug/mice) or by PBS for 10 days from day 1 to 5 and day 21 to 25. The clinical scores of CIA mice were assessed every two days from day 22 and determined on a scale of 0–4 for each paw. The proportion of ILC2 as well as Th1, Th2, Th17 and Treg in spleen, mesenteric lymph node (mLN) and joints of arthritic mice were analyzed by flow cytometry on day 42.Results:NMU-23 dramatically inhibited clinical onset and severity of arthritis in treated WT mice compared with control mice. Interestingly, NMU-deficient mice also developed significantly less severe arthritis compared with WT control (Fig 1). Flow cytometry analyses showed that the proportion of ILC2, which defined as Lin-CD45+CD127+KLRG1+ICOS+ST2+, was elevated in the joint but not in the spleen and mLN of arthritic mice treated with NMU-23. In contrast, the proportion of ILC2 was significantly lower in the spleen of NMU-deficient mice than WT control. The percentage of Th2 cells in the spleen and mLN tend to be higher in NMU-23 treated mice, but there is no statistical significance. Surprisingly, Th1 cells were increased in the mLN of NMU-23 treated and NMU-deficient mice compared with control whereas Th17 was comparable among groups. In addition, the proportion of Treg was decreased in the joint of NMU-23 treated and NMU-deficient mice compared with control mice.Conclusion:Our preliminary results show that repeated injection of NMU-23 during induction (early) and development (late) stage of CIA strongly suppressed clinical onset and severity of arthritis, which might be ascribed to activation of ILC2 in the joint. Further study is needed to explore other cellular and molecular mechanisms in the effect.References:[1] Cardoso V, Chesne J, Ribeiro H et al (2017) Neuronal regulation of type 2 innate lymphoid cells via neuromedin U. Nature 549 (7671):277-281.[2] Klose CSN, Mahlakoiv T, Moeller JB et al (2017) The neuropeptide neuromedin U stimulates innate lymphoid cells and type 2 inflammation. Nature 549 (7671):282-286.[3] Wallrapp A, Riesenfeld SJ, Burkett PR et al (2017) The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation. Nature 549 (7672):351-356.[4] Sindhuja M Rao, Jennifer L Auger, Philippe Gaillard et al (2012) The Neuropeptide Neuromedin U Promotes Autoantibody-Mediated Arthritis. Arthritis Res Ther, 14 (1), R29.Disclosure of Interests:None declared

scholarly journals Interleukin-33 and thymic stromal lymphopoietin, but not interleukin-25, are crucial for development of airway eosinophilia induced by chitin

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ken Arae ◽  
Masashi Ikutani ◽  
Kotaro Horiguchi ◽  
Sachiko Yamaguchi ◽  
Youji Okada ◽  
...  
Keyword(s):  
Allergic Diseases ◽  
Lymphoid Cells ◽  
House Dust Mites ◽  
Atopic Asthma ◽  
Th2 Cells ◽  
Airway Eosinophilia ◽  
Interleukin 33 ◽  
Group 2 ◽  
Underlying Mechanisms ◽  
Mechanisms Of Development

AbstractExposure to various antigens derived from house dust mites (HDM) is considered to be a risk factor for development of certain allergic diseases such as atopic asthma, atopic dermatitis, rhinitis and conjunctivitis. Chitin is an insoluble polysaccharide (β-(1–4)-poly-N-acetyl-d-glucosamine) and a major component in the outer shell of HDMs. Mice exposed to chitin develop asthma-like airway eosinophilia. On the other hand, several lines of evidence show that the effects of chitin on immune responses are highly dependent on the size of chitin particles. In the present study, we show that chitin induced production of IL-33 and TSLP by alveolar and bronchial epithelial cells, respectively, in mice. IL-25, IL-33 and TSLP were reported to be important for group 2 innate lymphoid cell (ILC2)-, but not Th2 cell-, dependent airway eosinophilia in a certain model using chitin beads. Here, we show that—in our murine models—epithelial cell-derived IL-33 and TSLP, but not IL-25, were crucial for activation of resident lung Th2 cells as well as group 2 innate lymphoid cells (ILC2s) to produce IL-5, resulting in development of chitin-induced airway eosinophilia. Our findings provide further insight into the underlying mechanisms of development of HDM-mediated allergic disorders.

Structure-based virtual screening of natural compounds as potential anti-allergy agents against cytokine alarmins (TSLP and IL-33)

2021 ◽  
Vol 18 ◽  
Author(s):  
Rahma Muhammad Adamu ◽  
Rita Singh Majumdhar ◽  
Abdullahi Ibrahim Uba
Keyword(s):  
Virtual Screening ◽  
Natural Product ◽  
In Silico ◽  
Early Stage ◽  
Allergic Inflammation ◽  
Prediction Method ◽  
Allergic Diseases ◽  
Natural Compounds ◽  
Dynamics Simulation ◽  
Th2 Cells

Background: Allergic diseases are turning into an expanding occurrence around the globe, imposing a socioeconomic burden, causing grimness and even death. Allergen encounter initiates the influx of TH2 cells, triggering the production of TH2 associated cytokines (IL-4, IL-5, and IL-13), which in turn promotes the detrimental allergic inflammation associated with asthma, allergic rhinitis, food allergy, urticaria, atopic eczema, and anaphylaxis. Cytokine alarmins (TSLP and IL-33) produced by epithelial cells play important roles in the promotion of TH2 cell development and the initiation of allergic pathogenesis. Objectives: The objective of this study is to target cytokine alarmins (TSLP and IL-33) as novel therapeutic proteins using natural compounds as a potential cure at an early stage of allergic diseases. Methods: Structure-based virtual screening of two large natural compounds databases (Universal Natural product Database (UNPD) and ZINC natural product database) was conducted for identification of TSLP and IL-33 inhibitors using Autodock Vina followed by rescoring of the hit compounds using Autodock 4.2 software. In silico physicochemical, pharmacokinetic, and toxicity analyses were conducted to assess the drug-like properties of the hit compounds. The binding mode stability of UNPD116849, ZINC01448143, and ZINC04096134 in the binding pocket of TSLP and IL-33 was probed by all-atom 50 ns molecular dynamics simulation. Results: Five natural compounds (UNPD111, UNPD116849, ZINC01448143, ZINC15957528, and ZINC04096134) containing different structural moieties (steroidal, chromone, benzodioxole, and indole), were identified to inhibit TSLP and IL-33, with limonin (ZINC04096134) found to demonstrate dual inhibitory activity potential. These compounds were found to be drug-like and toxicity-free using in silico Absorption, Distribution, Metabolism, Elimination, and Toxicity (ADME-T) prediction method. Taken together, this study suggests the dual inhibition potential of limonin (ZINC04096134) against the cytokine alarmins. Conclusion: Five natural compounds with diverse structural moieties (steroidal, chromone, benzodioxole, and indole) were virtually identified as hits compounds against cytokine alarmins (TSLP and IL-33), with limonin showing dual inhibitory potential.

scholarly journals Flemingia philippinensis Flavonoids Relieve Bone Erosion and Inflammatory Mediators in CIA Mice by Downregulating NF-κB and MAPK Pathways

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Guangchen Sun ◽  
Congcong Xing ◽  
Luting Zeng ◽  
Yijie Huang ◽  
Xin Sun ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Inflammatory Mediators ◽  
Bone Erosion ◽  
Collagen Induced Arthritis ◽  
Mapk Pathways ◽  
Mitogen Activated Protein ◽  
Anti Inflammatory ◽  
Inflammatory Effect

Background. The dry root of Flemingia philippinensis has been widely used in the treatment of rheumatism, arthropathy, and osteoporosis in traditional Chinese medicine; the therapeutic effects of Flemingia philippinensis are associated with antiarthritis in traditional Chinese medicine theory. This study was undertaken to investigate the mechanism of bone erosion protection and anti-inflammatory effect of Flemingia philippinensis flavonoids (FPF) in collagen-induced arthritis (CIA) in mice. Methods. Flavonoids were extracted from the dry root of Flemingia philippinensis. Collagen-induced arthritis in C57BL/6 mice was used as a rheumatoid arthritis model, and the mice were orally fed with FPF prior to induction to mimic clinical prophylactic therapy for a total of 39 days. After treatment, histology and immunohistochemistry staining were performed, and the levels of anti-collagen type II (CII) antibody and inflammatory mediators, as well as the key proteins of nuclear factor kappa-B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways, were detected in the samples taken from ankle joints, plasma, and paws. Results. FPF administration significantly suppressed the paw swelling and arthritic score in CIA mice. FPF reduced inflammatory infiltration and pannus formation, articular cartilage destruction and osteoclast infiltration, and the expression of MMP-9 and cathepsin K in the ankle joint. FPF inhibited plasma anti-CII antibody levels and the production of inflammatory cytokines and chemokines in CIA paws. FPF treatment suppressed the activation of NF-κB as indicated by downregulating the phosphorylation of NF-κB p65 and mitogen-activated protein kinases in CIA paws. Additionally, FPF significantly inhibited inflammation signaling by suppressing the activation of activator protein-1 subset and signal transducers and activators of transcription 3 (STAT3). Conclusions. Our data suggest that FPF might be an active therapeutic agent for rheumatoid arthritis and the preventive effect of FPF on arthritis is attributable to an anti-inflammatory effect on CIA by preventing bone destruction, regulating inflammatory mediators, and suppressing NF-κB and MAPK signaling pathways.

scholarly journals EEG Fractal Analysis Reflects Brain Impairment after Stroke

Entropy ◽  
2021 ◽  
Vol 23 (5) ◽  
pp. 592
Author(s):  
Maria Rubega ◽  
Emanuela Formaggio ◽  
Franco Molteni ◽  
Eleonora Guanziroli ◽  
Roberto Di Marco ◽  
...  
Keyword(s):  
Early Stage ◽  
Brain Activity ◽  
Phase 1 ◽  
Behavioral Changes ◽  
Stroke Survivors ◽  
Eeg Signals ◽  
Novel Treatments ◽  
Fractal Measures ◽  
Underlying Mechanisms ◽  
Random Fluctuations

Stroke is the commonest cause of disability. Novel treatments require an improved understanding of the underlying mechanisms of recovery. Fractal approaches have demonstrated that a single metric can describe the complexity of seemingly random fluctuations of physiological signals. We hypothesize that fractal algorithms applied to electroencephalographic (EEG) signals may track brain impairment after stroke. Sixteen stroke survivors were studied in the hyperacute (<48 h) and in the acute phase (∼1 week after stroke), and 35 stroke survivors during the early subacute phase (from 8 days to 32 days and after ∼2 months after stroke): We compared resting-state EEG fractal changes using fractal measures (i.e., Higuchi Index, Tortuosity) with 11 healthy controls. Both Higuchi index and Tortuosity values were significantly lower after a stroke throughout the acute and early subacute stage compared to healthy subjects, reflecting a brain activity which is significantly less complex. These indices may be promising metrics to track behavioral changes in the very early stage after stroke. Our findings might contribute to the neurorehabilitation quest in identifying reliable biomarkers for a better tailoring of rehabilitation pathways.

scholarly journals Gout of feet and ankles in different disease durations: diagnostic value of single-source DECT and evaluation of urate deposition with a novel semi-quantitative DECT scoring system

2021 ◽  
Vol 61 (1) ◽  
Author(s):  
Jin Shang ◽  
Xiao-Hu Li ◽  
Shu-Qin Lu ◽  
Yi Shang ◽  
Lu-Lu Li ◽  
...  
Keyword(s):  
Scoring System ◽  
Diagnostic Performance ◽  
Disease Duration ◽  
Bone Erosion ◽  
Early Stage ◽  
Gouty Arthritis ◽  
Single Source ◽  
Crystal Deposition ◽  
Urate Crystal ◽  
Sensitivity Specificity

Abstract Objectives To investigate the diagnostic performance of single-source dual-energy computed tomography (DECT) based on gemstone spectral imaging technology (including Discovery CT750HD and Revolution CT) in patients with suspected feet/ankles gouty arthritis, and evaluate the urate deposition with a novel semi-quantitative DECT scoring system. Methods A total of 196 patients were consecutively included. Feet and ankles were evaluated in all patients by single-source DECT scan. The 2015 EULAR/ACR criteria were used as the reference for the diagnosis of gout. The sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) of DECT for the diagnosis of gout in the early (≤1 year), middle (1–3 years), and late (> 3 years) disease durations were calculated. Besides, a novel semi-quantitative DECT scoring system was assessed for the measurement of urate deposition, and the correlation between the scores and the clinical and serological data were also evaluated. Moreover, the influences of artifacts on the diagnostic performance of DECT were also determined. Results The sensitivity, specificity, and AUC of DECT in 196 patients were 38.10, 96.43%, and 0.673 in the early-stage group; 62.96, 100.00%, and 0.815 in the middle-stage group; and 77.55, 87.50%, and 0.825 in the late-stage group, respectively. The overall diagnostic accuracies in the AUC of DECT (Discovery CT750HD and Revolution CT) in the middle and late stages of gout were higher than that in the early stage of gout. Besides, the monosodium urate crystals were deposited on the first metatarsophalangeal joints and ankles/midfeet. Age, the presence of tophus, bone erosion, and disease duration considerably affected the total urate score. No statistical difference in the positive detection of nail artifact, skin artifact, vascular calcification, and noise artifact was found between the case and control groups. Conclusion DECT (Discovery CT750HD and Revolution CT) showed promising diagnostic accuracy for the detection of urate crystal deposition in gout but had limited diagnostic sensitivity for short-stage gout. Longer disease duration, the presence of tophus, and bone erosion were associated with the urate crystal score system. The artifacts do not remarkably affect the diagnostic performance of DECT in gout.

scholarly journals In vitro evidence for the involvement of H2S pathway in the effect of clodronate during inflammatory response

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Rosangela Montanaro ◽  
Alessio D’Addona ◽  
Andrea Izzo ◽  
Carlo Ruosi ◽  
Vincenzo Brancaleone
Keyword(s):  
Inflammatory Markers ◽  
In Vitro Study ◽  
Inos Expression ◽  
Beneficial Effects ◽  
Tnf Α ◽  
Inflammatory State ◽  
Anti Inflammatory ◽  
Underlying Mechanisms ◽  
Inflammatory Effect

AbstractClodronate is a bisphosphonate agent commonly used as anti-osteoporotic drug. Throughout its use, additional anti-inflammatory and analgesic properties have been reported, although the benefits described in the literature could not solely relate to their inhibition of bone resorption. Thus, the purpose of our in vitro study is to investigate whether there are underlying mechanisms explaining the anti-inflammatory effect of clodronate and possibly involving hydrogen sulphide (H2S). Immortalised fibroblast-like synoviocyte cells (K4IM) were cultured and treated with clodronate in presence of TNF-α. Clodronate significantly modulated iNOS expression elicited by TNF-α. Inflammatory markers induced by TNF-α, including IL-1, IL-6, MCP-1 and RANTES, were also suppressed following administration of clodronate. Furthermore, the reduction in enzymatic biosynthesis of CSE-derived H2S, together with the reduction in CSE expression associated with TNF-α treatment, was reverted by clodronate, thus rescuing endogenous H2S pathway activity. Clodronate displays antinflammatory properties through the modulation of H2S pathway and cytokines levels, thus assuring the control of the inflammatory state. Although further investigation is needed to stress out how clodronate exerts its control on H2S pathway, here we showed for the first the involvement of H2S in the additive beneficial effects observed following clodronate therapy.

scholarly journals Pulsed Electromagnetic Field Inhibits Synovitis via Enhancing the Efferocytosis of Macrophages

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Junjie Ouyang ◽  
Bin Zhang ◽  
Liang Kuang ◽  
Peng Yang ◽  
Xiaolan Du ◽  
...  
Keyword(s):  
Medial Meniscus ◽  
Current Data ◽  
Pulsed Electromagnetic Field ◽  
Western Blot Assay ◽  
Anti Inflammatory ◽  
Pulsed Electromagnetic ◽  
Underlying Mechanisms ◽  
Pemf Treatment ◽  
Inflammatory Effect

Synovitis plays an important role in the pathogenesis of arthritis, which is closely related to the joint swell and pain of patients. The purpose of this study was to investigate the anti-inflammatory effects of pulsed electromagnetic fields (PEMF) on synovitis and its underlying mechanisms. Destabilization of the medial meniscus (DMM) model and air pouch inflammation model were established to induce synovitis in C57BL/6 mice. The mice were then treated by PEMF (pulse waveform, 1.5 mT, 75 Hz, 10% duty cycle). The synovitis scores as well as the levels of IL-1β and TNF-α suggested that PEMF reduced the severity of synovitis in vivo. Moreover, the proportion of neutrophils in the synovial-like layer was decreased, while the proportion of macrophages increased after PEMF treatment. In addition, the phagocytosis of apoptotic neutrophils by macrophages (efferocytosis) was enhanced by PEMF. Furthermore, the data from western blot assay showed that the phosphorylation of P38 was inhibited by PEMF. In conclusion, our current data show that PEMF noninvasively exhibits the anti-inflammatory effect on synovitis via upregulation of the efferocytosis in macrophages, which may be involved in the phosphorylation of P38.

Evaluation of inflammatory change and bone erosion using a murine type II collagen-induced arthritis model

2010 ◽  
Vol 31 (5) ◽  
pp. 595-603 ◽  
Author(s):  
Samjin Choi ◽  
Yeon-Ah Lee ◽  
Seung-Jae Hong ◽  
Gi-Ja Lee ◽  
Sung Wook Kang ◽  
...  
Keyword(s):  
Bone Erosion ◽  
Type Ii Collagen ◽  
Inflammatory Change ◽  
Type Ii ◽  
Collagen Induced Arthritis ◽  
Arthritis Model
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