CXCR4 inhibitor attenuates ovalbumin-induced airway inflammation and hyperresponsiveness by inhibiting Th17 and Tc17 cell immune response

Chen, Huilong; Xu, Xiangqin; Teng, Jieming; Cheng, Sheng; Bunjhoo, Hansvin; Cao, Yong; Jin, Liu; Xie, Jungang; Wang, Cong Yi; Xu, Yongjian; Xiong, Weining

doi:10.3892/etm.2016.3141

Cited by 28 publications

(18 citation statements)

References 29 publications

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“…The synergism of SDF-1α and CXCR4 is crucial at the early stage of inflammation, where they act to control lymphocyte mobilization [ 31 ]. The inhibition of CXCR4 could significantly reduce the inflammation cytokines and cells [ 32 ]. There are several reports in the literature that confirm an inflammation reaction in mild TBI [ 33 , 34 ].…”

Section: Discussionmentioning

confidence: 99%

Relationship of Circulating CXCR4+ EPC with Prognosis of Mild Traumatic Brain Injury Patients

Lin¹,

Luo²,

Sun³

et al. 2017

Aging and disease

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To investigate the changes of circulating endothelial progenitor cells (EPCs) and stromal cell-derived factor-1α (SDF-1α)/CXCR4 expression in patients with mild traumatic brain injury (TBI) and the correlation between EPC level and the prognosis of mild TBI. 72 TBI patients (57 mild TBI, 15 moderate TBI patients) and 25 healthy subjects (control) were included. The number of circulating EPCs, CD34+, and CD133+ cells and the percentage of CXCR4+ cells in each cell population at 1,4,7,14,21 days after TBI were counted by flow cytometer. SDF-1α levels in serum were detected by ELISA assay. The patients were divided into poor and good prognosis groups based on Extended Glasgow Outcome Scale and Activity of Daily Living Scale at 3 months after TBI. Correlation analysis between each detected index and prognosis of mild TBI was performed. Moderate TBI patients have higher levels of SDF-1α and CXCR4 expression than mild TBI patients (P < 0.05). The percentage of CXCR4+ EPCs at day 7 post-TBI was significantly higher in mild TBI patients with poor prognosis than the ones with good prognosis (P < 0.05). HAMA and HAMD scores in mild TBI patients were significantly lower than moderate TBI patients (P < 0.05) in early term. The percentage of CXCR4+ EPCs at day 7 after TBI was significantly correlated with the prognosis outcome at 3 months. The mobilization of circulating EPCs can be induced in mild TBI. The expression of CXCR4+ in EPCs at 7 days after TBI reflects the short-term prognosis of brain injury, and could be a potential biological marker for prognosis prediction of mild TBI.

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Section: Discussionmentioning

confidence: 99%

Relationship of Circulating CXCR4+ EPC with Prognosis of Mild Traumatic Brain Injury Patients

Lin¹,

Luo²,

Sun³

et al. 2017

Aging and disease

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“…Both peptides were more potent that AMD3100, which has previously been shown to attenuate allergen-induced infiltration of inflammatory cells into the airways 26,56,57 . The mechanism(s) underlying CXCR4-mediated inhibition of asthma are not fully understood, but may involve CXCR4-mediated suppression of inflammatory cell (mainly eosinophil) migration 22,24,25 , reduced expression of matrix metalloproteinase MMP-9 that drives airway remodeling 56 , or specific inhibition of CXCR4-expressing neutrophils or eosinophils releasing extracellular traps involved in asthma pathology 22,58 . Eosinophils are main contributors to the development of bronchial asthma and its exacerbations 54,58 .…”

Section: Epi-x4 Jm#21 Prevents Skin Inflammation In a Murine Model Ofmentioning

confidence: 83%

An optimized derivative of an endogenous CXCR4 antagonist prevents atopic dermatitis and airway inflammation

Harms

Habib

Nemska

et al. 2020

Preprint

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BackgroundAberrant CXCR4/CXCL12 signaling is involved in many pathophysiological processes including chronic inflammatory diseases. Thus, the chemokine receptor CXCR4 is a promising target for the therapy of inflammatory disorders, such as atopic dermatitis or allergic asthma. A natural fragment of serum albumin, named EPI-X4, has previous been identified as endogenous peptide antagonist and inverse agonist of CXCR4. The endogenous CXCR4 antagonist provides a promising basis for the development of improved analogues for the therapy of inflammatory diseases.ObjectiveTo increase the anti-CXCR4 activity of EPI-X4 and to evaluate the therapeutic potential of optimized analogs in mouse models of atopic dermatitis and asthma.MethodsMolecular docking analysis of the interaction of EPI-X4 with CXCR4 was performed to define critical interaction motifs and to rationally design analogs with increased activity. EPI-X4 derivatives were synthesized and CXCR4 binding and antagonizing activity determined in assays for antibody competition, inhibition of CXCR4-mediated HIV-1 infection, CXCL12-dependent Ca2+ mobilization, ERK and AKT phosphorylation and cell migration. Toxicity of peptides was evaluated in zebrafish embryos. The therapeutic efficacy of the lead peptide EPI-X4 JM#21 was determined in mouse models of atopic dermatitis and asthma.ResultsDocking analysis identified key interaction motifs of EPI-X4/CXCR4. Rational drug design allowed to increase the anti-CXCR4 activity of EPI-X4 and resulted in the generation of the lead analog JM#21, which bound CXCR4 and suppressed CXCR4-tropic HIV-1 infection more efficiently than the clinically approved small molecule CXCR4 antagonist AMD3100. JM#21 did not exert toxic effects in zebrafish embryos and efficiently prevented inflammation of the skin in a mouse model of atopic dermatitis. Moreover, EPI-X4 and its improved derivative suppressed allergen-induced infiltration of eosinophils and other immune cells into the airways of animals in an asthma mouse model.ConclusionThe rationally designed EPI-X4 derivative JM#21 is a potent antagonist of CXCR4 and the first CXCR4 inhibitor with therapeutic efficacy in atopic dermatitis. Further clinical development of this new class of CXCR4 antagonists for the therapy of atopic dermatitis, asthma and other CXCR4-associated diseases is highly warranted.Graphical Abstract

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“…Although asthma is a notoriously heterogeneous disease, emerging evidence has suggested that CD4 + T cells, such as Th1, Th2, Th9, Th17 and Treg cells, play a crucial role in the development of asthma . These cells can produce the majority of the known cytokines, such as IFN‐γ from Th1 cells; IL‐4, IL‐5, IL‐9, IL‐6 and IL‐13 from Th2 cells; and IL‐17A and IL‐17F from Th17 cells, which comprise a complex network that regulates the intricate immune response in asthma …”

Section: Discussionmentioning

confidence: 99%

Hsa_circ_0005519 increases IL‐13/IL‐6 by regulating hsa‐let‐7a‐5p in CD4⁺ T cells to affect asthma

Huang

Cao

Zhou

et al. 2019

Clin Experimental Allergy

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Background: Circular RNAs (circRNAs) are a class of non-coding RNAs that could serve as novel biomarkers for the diagnosis and treatment of diseases. We hypothesized that circRNAs of CD4 + T cells are involved in asthma. Objective:In this study, we investigated the circRNA expression profile and the possible mechanism by which hsa_circ_0005519 participates in asthma. Methods:The expression profiles of circRNAs in CD4 + T cells were revealed by circRNA microarray. Hsa_circ_0005519 expression in CD4 + T cells was confirmed in asthmatic patients (n = 65) and healthy subjects (n = 30). Hsa-let-7a-5p, the target of hsa_circ_0005519, was predicted by online algorithms and verified by a dual-luciferase reporter assay. Correlation assays between the expression of hsa_ circ_0005519 and hsa-let-7a-5p, the mRNA levels of interleukin (IL)-13 and IL-6 in CD4 + T cells, and the clinical characteristics of asthmatic patients were performed.The role of hsa_circ_0005519 in proinflammatory cytokine expression was investigated in CD4 + T cells from asthmatic patients in vitro. Hsa_circ_0005519 expression in PBMCs was determined in another cohort including 30 asthmatic patients and 24 controls. Correlation assays of hsa_circ_0005519 expressions between CD4 + T cells and PBMCs were performed.Results: Hsa_circ_0005519 was up-regulated and negatively correlated with hsalet-7a-5p expression in CD4 + T cells of asthmatic patients. Both the fraction of exhaled nitric oxide (FeNO) and the peripheral blood eosinophil ratio were positively correlated with hsa_circ_0005519 expression in CD4 + T cells. These outcomes were also different in asthmatic patients with low vs high hsa_circ_0005519 levels. Hsa_ circ_0005519 expressions between CD4 + T cells and PBMCs were concordant in asthmatic patients. Mechanistically, hsa_circ_0005519 might bind to hsa-let-7a-5p and relieve suppression for IL-13/IL-6 in CD4 + T cells. Conclusions and clinical relevance:Our data suggest that hsa_circ_0005519 may induce IL-13 and IL-6 expression by regulating hsa-let-7a-5p in CD4 + T cells to affect asthma. And hsa_circ_0005519 may be a potential biomarker of asthma. K E Y W O R D Sasthma, CD4 + T cells, hsa_circ_0005519, hsa-let-7a-5p, PBMCs

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CXCR4 inhibitor attenuates ovalbumin-induced airway inflammation and hyperresponsiveness by inhibiting Th17 and Tc17 cell immune response

Cited by 28 publications

References 29 publications

Relationship of Circulating CXCR4+ EPC with Prognosis of Mild Traumatic Brain Injury Patients

Relationship of Circulating CXCR4+ EPC with Prognosis of Mild Traumatic Brain Injury Patients

An optimized derivative of an endogenous CXCR4 antagonist prevents atopic dermatitis and airway inflammation

Hsa_circ_0005519 increases IL‐13/IL‐6 by regulating hsa‐let‐7a‐5p in CD4⁺ T cells to affect asthma

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CXCR4 inhibitor attenuates ovalbumin-induced airway inflammation and hyperresponsiveness by inhibiting Th17 and Tc17 cell immune response

Cited by 28 publications

References 29 publications

Relationship of Circulating CXCR4+ EPC with Prognosis of Mild Traumatic Brain Injury Patients

Relationship of Circulating CXCR4+ EPC with Prognosis of Mild Traumatic Brain Injury Patients

An optimized derivative of an endogenous CXCR4 antagonist prevents atopic dermatitis and airway inflammation

Hsa_circ_0005519 increases IL‐13/IL‐6 by regulating hsa‐let‐7a‐5p in CD4+ T cells to affect asthma

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About

Hsa_circ_0005519 increases IL‐13/IL‐6 by regulating hsa‐let‐7a‐5p in CD4⁺ T cells to affect asthma