JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
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2025
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IF 11.2
Yue Li,Zhengrong Chen,Miaomiao Han,Zhen Duan,Ruizhe Li,Xinyi Cui,Haiyan Ge,Yilai Shu,Huabin Li,Rui He
Background Plasmacytoid dendritic cells (pDCs) are previously reported to induce immune tolerance to allergen by inhibiting allergic Th2 cell priming. However, there is limited knowledge on pDC function during Th2 effector phase of allergic asthma. Objective We aimed to investigate the role of pDCs in ongoing allergic asthma following airway sensitization and challenge with house mite dust (HDM). Methods BDCA2-DTR mice were used for pDC depletion. RNA-sequencing (RNA-seq) of sorted mouse lung pDCs, in vitro cell experiments, and in vivo CCR2 blockade or Tβ4 supplementation were performed to elucidate the underlying mechanism. Results: pDC depletion during HDM challenge enhanced CCR2-dependent inflammatory monocyte-derived cells (inf-MCs) accumulation, leading to exacerbated Th2-mediated allergic asthma phenotypes. RNA-seq analysis revealed an anti-inflammatory peptide thymosin β4 (Tβ4) among the most up-regulated genes in asthmatic lung pDCs. Airway epithelial cells-derived IL-33 was required for up-regulating Tβ4 expression in pDCs, which represented the main source of Tβ4 in asthmatic lungs. Importantly, Tβ4 supplementation reversed the exacerbation of asthmatic phenotypes in BDCA2-DTR mice. Alveolar macrophages were identified as the major source of CCL2 and the target of Tβ4 in asthmatic lungs. Mechanistically, Tβ4 inhibited IL-4/IL-13-induced phosphorylation of JAK1 and STAT6 and downstream EGR2 expression in macrophages, thereby reducing CCL2 expression and subsequent inf-MC recruitment. Unexpectedly, decreased serum Tβ4 levels were detected in mice and humans with ongoing allergic asthma. This could be due to increased uptake of Tβ4 by alveolar macrophage, which was required for its inhibitory effect on CCL2 expression. Conclusions Lung pDCs exert anti-inflammatory effects in allergic asthma via expressing Tβ4, which could have therapeutic potential.
研究领域:
免疫学
·
呼吸病学
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DOI
PubMed
高影响因子
TUMOR BIOLOGY
·
2016
·Vol. 37
·期 7
·8609-8619
·
IF 2.926
Xu Jinfeng,Zeng Xinxin,Liu Yingying,Luo Hui,Wei Zhanghong,Liu Huiyu,Zhou Yuli,Zheng Hairong,Zhou Jie,Tan Guanghong,Yan Fei
Ultrasound-targeted microbubble destruction (UTMD) has become a novel gene/drug delivery method in cancer therapeutic application. However, the gene transfection efficiency mediated by UTMD is still unsatisfactory. Here, we introduced iRGD/CCR2 dual-targeted cationic microbubbles (MB iRGD/CCR2 ) which was modified with PEI-600 and coated with iRGD peptides and anti-CCR-2 antibodies. It showed that MB iRGD/CCR2 had a 25.83 ± 1.57 mV surface zeta potential and good stability. The experiments in vitro showed MB iRGD/CCR2 had higher binding efficiency with both bEnd.3 cells and MCF-7 cells than that of iRGD or CCR2 single-targeted cationic microbubbles (MB iRGD or MB CCR2 ) ( P < 0.05 for both). Agarose gel electrophoresis assay showed that MB iRGD/CCR2 can effectively load pGPU6/GFP/Neo-shAKT2 plasmid DNA. Compared with the plain MBs (MB control ) or single-targeted cationic MBs including MB iRGD and MB CCR2 ( P < 0.05 for all), the dual-targeted cationic MB iRGD/CCR2 groups had higher gene transfection efficiency under US exposure. It showed that the dual-targeted cationic MB iRGD/CCR2 has a potential value to be used as an ultrasound imaging probe for ultrasound image-guided tumor gene therapy.
研究领域:
医学影像
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基因治疗
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癌症研究
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超声技术
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PubMed
高影响因子
Redox Biology
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2026
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IF 16.2
Zhengyi Chen,Xidan Fu,Chao Liu,Wenkang Jiang,Jiurong Liu,Miao Hao,Ling Fu,Wei Huang,Xiujuan Lang,Xijun Liu,Yumei Liu,Hulun Li,Rui Li,Bo Sun
Aging reshapes hematopoiesis toward myelopoiesis, particularly increased output of classical monocytes, contributing to immunosenescence. However, the underlying mechanisms remain unclear. Here, we identify that aging drives hematopoietic stem cells (HSCs) to progressively commit to a CCR2 + monocyte fate along a defined lineage trajectory, which is executed through a redox-sensitive transcriptional cascade. We find that the age-related decline in bone marrow IGF-1 is the upstream niche signal that releases suppression of the oxidative stress/NF-κB/IRF8 axis, allowing this cascade to redirect early progenitors toward a CCR2 + myeloid-primed fate. Functional assays confirm that cells following this CCR2 + trajectory drive myeloid-biased hematopoiesis and directly contribute to age-associated immunosuppression. Our work delineates a hierarchical pathway from niche decay to lineage redirection, establishing the CCR2 + fate trajectory as a key driver of immunosenescence and a potential therapeutic target.
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高影响因子
Chinese Medicine
·
2026
·Vol. 21
·期 1
·96
·
IF 7.4
Xu Yu,Cai Jing,Fan Yuan-Ming,Qi Lian-Wen,Zhang Lei
Background Zhen-Wu-Tang (ZWT), a classic herbal formula from Treatise on Febrile and Miscellaneous Diseases, is commonly used for heart and kidney-related diseases. Despite its widespread application, research on the active components of ZWT and their mechanisms in heart–kidney cross-organ regulation remains underexplored. Aim of the study This study aimed to elucidate the therapeutic mechanisms of ZWT in uremic cardiomyopathy (UC) focusing on its modulation of the heart–kidney inflammatory axis. Materials and methods A UC model was established via 5/6 nephrectomy in mice, followed by 8 weeks of ZWT treatment. Functional assessments included serum creatinine, blood urea nitrogen, cardiac ejection fraction, and left ventricular metrics. Proteomic analysis using Olink technology exerts its therapeutic effects by suppressing systemic inflammation. UHPLC-Q/TOF–MS were employed to identify prototype components and blood-entering components in ZWT. Cellular experiments using a three-step co-culture system were conducted to evaluate the regulatory effects of ZWT active components on HK-2 and AC16 cells and to explore their underlying molecular mechanisms. Results ZWT significantly improved renal and cardiac functions. Proteomics revealed ZWT suppressed pro-inflammatory cytokines TNFα, IL-6, IL-1β and chemokines. The bioactive constituents of ZWT, including benzoylaconine, paeoniflorin, and atractylenolide III, inhibited NF-κB activation, thereby reducing CCL2 synthesis and subsequent macrophage recruitment via the CCR2 axis. This attenuated systemic inflammation and cardiomyocyte injury. Conclusions ZWT exerts therapeutic effects on UC by targeting the kidney-heart inflammatory axis and suppressing CCL2/CCR2-mediated macrophage activation. This study provides new insights into the molecular mechanisms underlying ZWT's efficacy in treating heart–kidney disorders.
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PubMed
高影响因子
Advanced Healthcare Materials
·
2024
·
IF 10
Haipeng Tan,Weiyan Li,Zhiqing Pang,Xueyi Weng,Jinfeng Gao,Jing Chen,Qiaozi Wang,Qiyu Li,Hongbo Yang,Zheng Dong,Zhengmin Wang,Guangrui Zhu,Yiwen Tan,Yuyuan Fu,Chengzhi Han,Shiteng Cai,Juying Qian,Zheyong Huang,Yanan Song,Junbo Ge
Efferocytosis, mediated by the macrophage receptor MerTK (myeloid-epithelial-reproductive tyrosine kinase), is a significant contributor to cardiac repair after myocardial ischemia-reperfusion (MI/R) injury. However, the death of resident cardiac macrophages (main effector cells), inactivation of MerTK (main effector receptor), and overexpression of “do not eat me” signals (brake signals, such as CD47), collectively lead to the impediment of efferocytosis in the post-MI/R heart. To date, therapeutic strategies targeting individual above obstacles are relatively lacking, let alone their effectiveness being limited due to constraints from the other concurrent two. Therefore, we aim to develop a strategy that challenges all three barriers in an integrated manner. Methods : We design a collaborative drug delivery strategy based on genetically modified macrophage therapy. The genetic engineering of exogenous macrophages involves overexpression of C-C chemokine receptor type 2 (CCR2) and cleavage-resistant MerTK (MerTK CR ) by adenovirus. Liposomes loaded with PEP-20 (a CD47 antagonist) are then anchored to the engineered macrophage surface by click chemistry. Results : CCR2 targets exogenous macrophages to the injured heart as a direct supplement to efferocytosis effector cells, while MerTK CR preserves functional intact locally. PEP-20 is responsively released to block the braking effect of CD47 on cardiac efferocytosis. In MI/R mice model, this synergistic strategy can effectively restore cardiac efferocytosis after intravenous injection, thereby alleviating the inflammatory response, ultimately preserving cardiac function. Conclusion : Genetically engineered macrophages co-loaded with CD47 inhibitors synergistically reconstruct efferocytosis and improve cardiac remodeling post MI/R injury. This article is protected by copyright. All rights reserved
研究领域:
心脏病学
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分子生物学
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药理学
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基因工程
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PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2025
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IF 4.7
Yi-Min Ren,Yu Chen,Chang-Mao Jiang,Xiong Chen,Hong-Jin Qin,Zhu Wei,Xue Rao,Yu-Chen Wang,Ning-Ze Jiang,Jin-Yuan Luo-Qian,Ying-Nan Song,Xiao-Hua Zou,Jiang Zheng,Hong-Jin Chen
Chronic inflammatory pain (CIP) poses a significant medical challenge, with current pharmacological treatments often associated with considerable side effects. The identification of effective therapeutic targets and the development of novel agents remain major hurdles. Exploring neuroimmune interactions and utilizing network pharmacology to uncover compounds capable of simultaneously modulating pain and inflammation presents a promising strategy. In this study, the therapeutic efficacy, potential targets, and underlying mechanisms of isoliquiritigenin (ISL) were investigated in a mouse model of CIP induced by complete Freund's adjuvant (CFA) paw pad injection. Single-dose ISL (20 or 60 mg/kg) attenuated CFA-induced hypersensitivity in an acute screening experiment, after which we investigated sustained efficacy using ISL (10 mg/kg) once daily for 7 days. ISL treatment significantly reduced paw swelling, mechanical allodynia, and thermal hyperalgesia. Additionally, ISL lowered the levels of IL-6, TNF-α, and VCAM-1 in both dorsal root ganglia (DRG) and skin tissues, along with a significant reduction in ERK phosphorylation. Network pharmacology analysis and molecular docking suggested CCR2 as a potential target of ISL. Further investigation revealed that ISL attenuated CCL7-induced CCR2 signaling activation. To validate the involvement of CCR2, siRNA-mediated knockdown of CCR2 was performed via DRG injection. This intervention suppressed ISL's analgesic and anti-inflammatory effects in CIP mice and CCL7 paw pad injection-induced pain and inflammation. Moreover, activation of ERK using tert-butylhydroquinone in CCR2 knockdown mice exacerbated CFA-induced inflammatory responses. These findings suggest that ISL alleviates CIP by targeting the CCL7/CCR2 axis and suppressing ERK-mediated inflammation.
研究领域:
药理学
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神经科学
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免疫学
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疼痛研究
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分子生物学
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PubMed
高影响因子
Research
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2022
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IF 11.036
Yanhong Wang,Fangchao Xue,Yanzhao Li,Lin Lin,Yeqin Wang,Shanlan Zhao,Xingli Zhao,Yong Liu,Ju Tan,Gang Li,Haoran Xiao,Juan Yan,Hao Tian,Min Liu,Qiao Zhang,Zhaojing Ba,Lang He,Wenyan Zhao,Chuhong Zhu,Wen Zeng
Rapid integration into the host tissue is critical for long-term patency after small diameter tissue engineering vascular grafts (sdTEVGs) transplantation. Neural recognition may be required for host integration and functionalization of the graft. However, immune rejection and inflammation hinder nerve regeneration of sdTEVGs. Here, a CRISPR/dCas9-nanocarrier was used for targeted programming of regulatory T cells (Treg cells) in situ to promote nerve regeneration of sdTEVGs by preventing excessive inflammation. Treg cells and (C-C chemokine receptor) CCR2+ macrophage recruitment occurred after transplantation. The nanodelivery system upregulated ten eleven translocation (TET2) in Treg cells in vitro. Reprogrammed Treg cells upregulated anti-inflammatory cytokines and decreased the proportion of CCR2+ macrophages. IL-6 concentrations decreased to the levels required for nerve regeneration. Implantation of CRISPR/dCas9 nanodelivery system-modified sdTEVGs in rats resulted in Treg cell editing, control of excessive inflammation, and promoted nerve regeneration. After 3 months, nerve regeneration was similar to that observed in normal blood vessels; good immune homeostasis, consistency of hemodynamics, and matrix regeneration were observed. Neural recognition promotes further integration of the graft into the host, with unobstructed blood vessels without intimal hyperplasia. Our findings provide new insights into vascular implant functionalization by the host.
研究领域:
生物医学工程
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免疫学
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组织工程
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分子生物学
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纳米技术
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PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
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2024
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IF 13.3
Yuxiao Wang,Guichun Wang,Jiaxin Li,Maomao Tang,Baoqing Jia,Zixuan Shu,Yang Ding,Chengjun Peng,Shuangying Gui,Jian Guo
Periodontitis is a chronic inflammatory disease caused by pathogenic biofilms and over-activated host immune response, leading to sustained damage to periodontal supporting tissue and even tooth loss. A key therapeutic challenge in recurrence of periodontitis is persistent existence of infiltrating monocytes and macrophages in periodontal tissues. Particularly, C-C motif ligand 2 (CCL2) is vital for monocyte recruitment and macrophage polarization in periodontitis. In this study, we developed biomimetic caffeic acid phenethyl ester-loaded nanoparticles (M−CNPs) as nanodecoys by macrophage membrane encapsulation to block CCL2-mediated inflammatory response and tissue damage. M−CNPs were distributed in the thermosensitive gel matrix (M−CNPs@Gel) to improve the retention time and sustained-release in the periodontal pocket. Our study demonstrated that M−CNPs@Gel exhibited a significant nanodecoy effect by competitively binding to CCL2 in periodontium, which inhibited monocyte/macrophages recruitment. Additionally, biomimetic nanodecoy system could reprogram macrophages phenotype through multi-step blocking CCL-CCR2-PI3K pathway and ROS elimination . M−CNPs@Gel effectively reduced the infiltration of monocytes and macrophages, and promote alveolar bone regeneration by regulating the ratio of M1/M2 macrophages in vivo . This study develops a novel CCL2-scavenging biomimetic nanodecoy hydrogel that remodel monocytes recruitment and macrophages polarization for effective periodontitis treatment.
研究领域:
牙科学
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药学
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生物医学工程
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免疫学
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高影响因子
JOURNAL OF CLINICAL INVESTIGATION
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2025
·Vol. 135
·期 2
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IF 13.6
Jiaqi Huang,Hao Liu,Zhujiang Liu,Zhenting Wang,Hanshi Xu,Zhuofan Li,Shan Huang,Xueyuan Yang,Yicong Shen,Fang Yu,Yulin Li,Junming Zhu,Wei Li,Li Wang,Wei Kong,Yi Fu
The pathogenesis of thoracic aortic aneurysm (TAA) in Marfan syndrome (MFS) is generally attributed to vascular smooth muscle cell (VSMC) pathologies. However, the role of immune cell–mediated inflammation remains elusive. Single-cell RNA sequencing identified a subset of CX3CR1+ macrophages mainly located in the intima in the aortic roots and ascending aortas of Fbn1C1041G/+ mice, further validated in MFS patients. Specific elimination of CX3CR1+ cells by diphtheria toxin in Cx3cr1-CreERT2iDTRF/+Fbn1C1041G/+ mice efficiently ameliorated TAA progression. Administering the monoclonal antibodies to respectively neutralize TNF-α and IGF1 produced by CX3CR1+ cells from MFS patients greatly suppressed the cocultured MFS patient–specific induced pluripotent stem cell–derived VSMC inflammation. BM transplantation and parabiosis revealed that CX3CR1+ macrophages are mainly originated from BM-derived monocytes. Targeting TNF-α and IGF1 in CX3CR1+ macrophages via shRNA lentivirus transduction in BM cells efficiently suppressed TAA development in BM-transplanted Fbn1C1041G/+ mice. Application of the CCR2 antagonist RS504393 to inhibit monocyte infiltration markedly reduced the accumulation of CX3CR1+ macrophages and subsequently alleviated TAA progression in Fbn1C1041G/+ mice. In summary, CX3CR1+ macrophages mainly located in aortic intima mediate TAA formation by paracrinally causing VSMC inflammation, and targeting them offers a potential antiinflammatory therapeutic strategy for MFS-related TAA.
研究领域:
心血管研究
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免疫学
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分子生物学
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遗传性疾病
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DOI
PubMed
高影响因子
Theranostics
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2025
·Vol. 15
·期 16
·8587
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IF 13.3
Wei-Jia Yu,Wen-Xi Jiang,Shu-Jing Liu,Hui-Hua Li,Qiu-Yue Lin
Rationale: Infiltration of immune cells into the heart plays a crucial role in the transition from adaptive hypertrophy to heart failure (HF) following chronic pressure overload. However, the key factors in myeloid cells that regulate this process are still not well defined. Here, we studied the functional role of S100A8/A9 in myeloid cells during this transition. Methods: Cardiac hypertrophy and HF models were induced by transverse aortic constriction (TAC) for 1 to 4 weeks. The heterogeneity of CD45 + immune cells and the cellular sources of S100A8/A9 were analyzed using published single-cell RNA sequencing datasets. The effects of S100A8/A9 on TAC-induced hypertrophy and HF were verified in S100A9 knockout (KO) and bone marrow (BM)-chimeric mice and in an in vitro coculture system. Results: S100A8/A9 levels were significantly increased in HF patients and in TAC-induced HF model mice. Moreover, the TAC-induced transition from adaptive hypertrophy to HF was significantly attenuated in S100A9-KO mice and WT mice transplanted with S100A9-KO BM cells. Mechanistically, TAC-stimulated upregulation of S100A8/A9 in neutrophils induced an early inflammatory response and adaptive hypertrophy through activation of the p38 MAPK/JNK/AP-1 pathway, leading to increased production of IL-1β and chemokines (CCL2 and CCL6). These chemokines promoted the infiltration of CCR2 + macrophages to the damaged heart. Therefore, they exhibited upregulation of S100A8/A9, which led to exacerbation of inflammation, cardiac hypertrophy and fibrosis via activation of the NF-κB/NLRP3, AKT/Calcineurin A and TGF-β/Smad2 signaling pathways. Additionally, treating WT mice with the S100A9 inhibitor ABR-238901 prevented TAC-induced cardiac hypertrophy-related dysfunction. Conclusion: The present findings establish an S100A8/A9-related axis between myeloid cells and cardiac cells that drives the pressure overload-induced transition from hypertrophy to HF, suggesting that S100A8/A9 is a promising therapeutic target for this disease.
研究领域:
心脏病学
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免疫学
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分子生物学
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基因组学
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生物医学研究
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PubMed
高影响因子
Advanced Science
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2024
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IF 14.3
Rong-Rong Lin,Lu-Lu Jin,Yan-Yan Xue,Zhe-Sheng Zhang,Hui-Feng Huang,Dian-Fu Chen,Qian Liu,Zheng-Wei Mao,Zhi-Ying Wu,Qing-Qing Tao
The blood brain barrier (BBB) limits the application of most therapeutic drugs for neurological diseases (NDs). Hybrid cell membrane-coated nanoparticles derived from different cell types can mimic the surface properties and functionalities of the source cells, further enhancing their targeting precision and therapeutic efficacy. Neuroinflammation has been increasingly recognized as a critical factor in the pathogenesis of various NDs, especially Alzheimer's disease (AD). In this study, a novel cell membrane coating is designed by hybridizing the membrane from platelets and chemokine (C–C motif) receptor 2 (CCR2) cells are overexpressed to cross the BBB and target neuroinflammatory lesions. Past unsuccessful endeavors in AD drug development underscore the challenge of achieving favorable outcomes when utilizing single-mechanism drugs.Two drugs with different mechanisms of actions into liposomes are successfully loaded to realize multitargeting treatment. In a transgenic mouse model for familial AD (5xFAD), the administration of these drug-loaded hybrid cell membrane liposomes results in a significant reduction in amyloid plaque deposition, neuroinflammation, and cognitive impairments. Collectively, the hybrid cell membrane-coated nanomaterials offer new opportunities for precise drug delivery and disease-specific targeting, which represent a versatile platform for targeted therapy in AD.
研究领域:
纳米技术
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神经科学
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药学
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生物医学工程
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PubMed
高影响因子
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