International Journal of Biological Sciences
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2022
·
IF 10.75
Li Zhang,Linyu Zhu,Xiaohan Yao,Xiaohan Lou,Jiajia Wan,Xixi Duan,Longze Pan,Anqi Li,Zhuoyu Gu,Ming Wang,Fazhan Wang,Zhihai Qin
Chemotherapeutic drugs have been successfully used to treat several cancers, including melanoma. However, metastasis occasionally occurs after chemotherapy. Here, we reported that paclitaxel (PTX) treatment for B16F10 tumour in mice led to an enhanced lymphatic metastasis of the melanoma cells, although a significant inhibition of tumour growth at the injection site was observed. Further study demonstrated that PTX upregulated the expression of C-C chemokine receptor type 7 (CCR7) in B16F10 cells, enhancing their migration through the activation of JNK and p38 signalling pathways. Loss of CCR7 or blockade of C-C motif chemokine ligand 21 (CCL21)/CCR7 axis abolished the pro-migration effect of PTX on B16F10 melanoma cells. Importantly, combination of PTX and CCR7 mAb could simultaneously delay the tumour growth and reduce the lymphatic metastasis in B16F10 melanoma. The blockade of CCL21/CCR7 axis may collectively serve as a strategy for lymphatic metastasis in some melanoma after chemotherapy.
研究领域:
肿瘤学
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免疫学
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药理学
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DOI
PubMed
高影响因子
IMMUNITY
·
2019
·
IF 21.522
Juan Liu,Xiaomin Zhang,Kun Chen,Yujie Cheng,Shuxun Liu,Meng Xia,Yali Chen,Ha Zhu,Zhiqing Li,Xuetao Cao
Summary CCR7 chemokine receptor stimulation induces rapid but transient dendritic cell (DC) migration toward draining lymph nodes, which is critical for the initiation of protective immunity and maintenance of immune homeostasis. The mechanisms for terminating CCR7-mediated DC migration remain incompletely understood. Here we have identified a long non-coding RNA lnc-Dpf3 whose feedback restrained CCR7-mediated DC migration. CCR7 stimulation upregulated lnc-Dpf3 via removing N6-methyladenosine (m 6 A) modification to prevent RNA degradation. DC-specific lnc-Dpf3 deficiency increased CCR7-mediated DC migration, leading to exaggerated adaptive immune responses and inflammatory injuries. Mechanistically, CCR7 stimulation activated the HIF-1α transcription factor pathway in DCs, leading to metabolic reprogramming toward glycolysis for DC migration. lnc-Dpf3 directly bound to HIF-1α and suppressed HIF-1α-dependent transcription of the glycolytic gene Ldha , thus inhibiting DC glycolytic metabolism and migratory capacity. We demonstrate a critical role for CCR7-inducible lnc-Dpf3 in coupling epigenetic and metabolic pathways to feedback-control DC migration and inflammatory responses.
研究领域:
免疫学
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分子生物学
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细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
Cellular & Molecular Immunology
·
2025
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IF 19.8
Bai Ying,Ren Hui,Leng Shuo,Yuan Mengqin,Jiang YiXin,Zhang Shenyang,Wang Yu,Ju Minzi,Wang Zhi,Xi Wen,Xu Lian,Zheng Bingjing,Li Daxing,Huo Xinchen,Zhu Tianhao,Zhang Beicheng,Shen Ling,Zhang Yuan,Jiang Wei,Zhang John H.,Han Bing,Yao Honghong
Splenic sympathetic activity critically modulates peripheral immunity after ischemic stroke, thus intervention in spleen sympathetic activity represents a promising therapeutic strategy for stroke. However, the mechanisms underlying spleen-brain-immune axis communication remain poorly understood. Here, we utilized a surgical denervation protocol to perform splenic sympathetic denervation (SDN), which significantly attenuated brain injury following stroke. Through single-cell RNA sequencing, we identified a novel GZMK + CD8 + CD27 + CCR7 + T-cell subset in patients with acute ischemic stroke (AIS), which we designated stroke-associated T (Tsa) cells. The expansion of Tsa cells was positively correlated with the severity of clinical symptoms and was driven by the splenic sympathetic nervous system. Stroke-induced sympathetic activation triggers the release of splenic norepinephrine (NE), which preferentially signals through ADRB2 on Tsa cells to promote their mobilization. Additionally, ischemic injury induces endothelial cell-specific expression of CCL19, which chemoattracts Tsa cells into the brain parenchyma via their cognate CCR7 receptor, exacerbating neuroinflammatory injury and neurological deficits in a transient middle cerebral artery occlusion (tMCAO) mouse model. We developed a CCR7-targeting peptide to disrupt this chemotactic axis and reduce T-cell infiltration, thereby mitigating brain injury. Our findings highlight SDN as a promising therapeutic strategy to attenuate ischemia‒reperfusion injury and suggest its potential as an adjunctive therapy for reperfusion treatment in AIS patients.
研究领域:
神经科学
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免疫学
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卒中研究
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神经免疫学
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分子生物学
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细胞生物学
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生物医学研究
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药理学
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系统生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Acta Pharmaceutica Sinica B
·
2025
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IF 14.6
Wenxiang Hong,Hongbo Ma,Zhaoxu Yang,Jiaying Wang,Bowen Peng,Longling Wang,Yiwen Du,Lijun Yang,Lijiang Zhang,Zhibin Li,Han Huang,Difeng Zhu,Bo Yang,Qiaojun He,Jiajia Wang,Qinjie Weng
Dendritic cells (DCs) serve as the primary antigen-presenting cells in autoimmune diseases, like rheumatoid arthritis (RA), and exhibit distinct signaling profiles due to antigenic diversity. Type II collagen (CII) has been recognized as an RA-specific antigen; however, little is known about CII-stimulated DCs, limiting the development of RA-specific therapeutic interventions. In this study, we show that CII-stimulated DCs display a preferential gene expression profile associated with migration, offering a new perspective for targeting DC migration in RA treatment. Then, saikosaponin D (SSD) was identified as a compound capable of blocking CII-induced DC migration and effectively ameliorating arthritis. Optineurin (OPTN) is further revealed as a potential SSD target, with Optn deletion impairing CII-pulsed DC migration without affecting maturation. Function analyses uncover that OPTN prevents the proteasomal transport and ubiquitin-dependent degradation of C–C chemokine receptor 7 (CCR7), a pivotal chemokine receptor in DC migration. Optn -deficient DCs exhibit reduced CCR7 expression, leading to slower migration in CII-surrounded environment, thus alleviating arthritis progression. Our findings underscore the significance of antigen-specific DC activation in RA and suggest OPTN is a crucial regulator of CII-specific DC migration. OPTN emerges as a promising drug target for RA, potentially offering significant value for the therapeutic management of RA.
研究领域:
免疫学
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风湿病学
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药理学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2022
·Vol. 11
·期 22
·2201166
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IF 11.092
Yueyang Deng,Caixia Tan,Shuguang Huang,Honghao Sun,Zhaoting Li,Jing Li,Zhanwei Zhou,Minjie Sun
Tumor metastasis contributes to high cancer mortality. Tumor cells in lymph nodes (LNs) are difficult to eliminate but underlie uncontrollable systemic metastasis. The CC chemokine receptor 7 (CCR7) is overexpressed in tumor cells and interacts with CC chemokine ligand 21 (CCL21) secreted from LNs, potentiating their lymphatic migration. Here, a site-specific polyplex is developed to block the CCR7-CCL21 signal and kill tumor cells toward LNs, greatly limiting their lymphatic infiltration. A CCR7-targeting small interfering RNA (siCCR7) is condensed by mPEG-poly-(lysine) with chlorin e6 (Ce6) modification (PPLC) to form PPLC/siCCR7. The knockdown of CCR7 by siCCR7 in tumor cells significantly reduced their response on CCL21 and LN tropism. Additionally, photodynamic therapy-mediated immune activation precisely targets and kills tumor cells released from the primary foci before they reaches the LNs, reducing the number of tumor cells entering the LNs. Consequently, the PPLC/siCCR7 polyplexes inhibited up to 92% of lung metastasis in 4T1 tumor bearing mice and reduced tumor cell migration to LNs by up to 80%. This site-specific strategy optimized anti-metastasis efficacy and promotes the clinical translational development of anti-metastatic therapy.
研究领域:
肿瘤学
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分子生物学
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免疫学
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药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Communication and Signaling
·
2026
·Vol. 24
·期 1
·378
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IF 11.6
Ouyang Miao,Wang Jianhui,Luo Xiaoguang,Tian Ruilin
Cells must continuously sense and respond to environmental changes by translating physical and chemical cues into intracellular signals. However, systematic discovery of genes governing these sensory processes has been limited by the transient nature of signaling events and the low throughput of measurement assays. Here, we present CaRPOOL, a pooled, high‑throughput genetic screening platform that integrates the calcium‑activity recorder CaMPARI2 with CRISPR interference (CRISPRi), enabling stable capture of transient calcium signals for genome‑scale functional screening. Using osmomechanical stimulation as a model, we demonstrate that CaMPARI2 photoconversion faithfully reports stimulus‑dependent calcium responses and supports pooled fluorescence‑activated cell sorting (FACS)–based screening. A CRISPRi library targeting membrane‑associated genes identified both known and previously uncharacterized regulators of osmomechanosensing, including the chemokine receptor CCR7. Mechanistic analyses revealed that CCR7 promotes osmomechanical calcium signaling through a PIEZO1‑dependent Gαs–cAMP–PKA pathway, establishing it as a GPCR regulator of osmomechanical response. Notably, osmotic stress upregulated CCR7 expression in immune cell lines and enhanced osmomechanical responsiveness, suggesting a role in osmomechanical adaptation. Together, these findings introduce a broadly applicable platform for high‑throughput discovery of genes controlling dynamic signaling responses and reveal a GPCR–ion channel crosstalk mechanism in osmomechanotransduction with potential implications for immune cell mechanoadaptation.
✓ 已验证
DOI
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
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2026
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IF 15
Yamei Gao,Xueting Shen,Jiliang Lu,Chaojing Zhou,Shaohu Huo,Ziyue Diao,Chao Chen,Xin Han,Zhiqiang Yin
Inflammatory skin diseases (ISDs) pose a major global burden, yet current therapies are limited by efficacy, accessibility, and cost, necessitating novel effective treatments. Thus, our study proposes a novel synergistic therapeutic strategy for psoriasis (PSO) and atopic dermatitis (AD) by concurrently targeting two critical pathological axes: immune cell chemotaxis via CCR7 inhibition and local inflammatory signaling via JAK1 suppression. A pH-responsive hydrogel (C-P@U/C-siCCR7) was designed for co-delivery of CCR7-targeting siRNA and the JAK1 inhibitor upadacitinib (UPA). Multi-omics analysis confirmed specific CCR7 overexpression in patient and model tissues. In vitro, the system inhibited keratinocyte proliferation, induced apoptosis, and downregulated key proteins in the JAK-STAT and PI3K/AKT/mTOR pathways along with pro-inflammatory cytokines. In IMQ-induced PSO and DNCB-induced AD mouse models, topical hydrogel application ameliorated skin lesions, restored the epidermal barrier, reduced hyperplasia and infiltration, and alleviated systemic immune activation-including suppression of splenomegaly and serum cytokines (IL17A, TNFα, IL4, IL13)-with favorable biosafety. The therapeutic effects were mechanistically linked to synergistic downregulation of CCR7, JAK1, STAT3, and mTOR in lesions, and reduced populations of aberrantly activated T cells, neutrophils, and dendritic cells in the spleen. This work provides a novel delivery platform and experimental evidence for developing effective, precise topical combination therapies against ISDs.
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2023
·
IF 8.2
Sitian Li,Yongtao Wang,Huaiqing Jiang,Yueyue Bai,Tao Chen,Min Chen,Mengze Ma,Shenyu Yang,Yan Wu,Chaochen Shi,Fazhan Wang,Yazhou Chen
CCL21, a secondary lymphoid tissue chemokine, plays an important role in generating an effective anti-tumor immune response. In this study, a genetically modified CCL21 was developed by inserting a pH low insertion peptide to establish a CCL21-rich microenvironment for tumors. The fusion tag thioredoxin (Trx) was designed and fused at the N-terminal of the recombinant protein to protect it from being irrevocably misfolded in microbial host cells. The prokaryotic expression vector pET32a-CCL21-pHLIP was constructed and successfully expressed in E. coli BL21 (DE3) with a soluble expression form and a molecular weight of ~35 kDa. The induction conditions were optimized to obtain an extremely high yield of 6.7 mg target protein from 31.1 mg total protein. The 6xHis tagged Trx-CCL21-pHLIP was purified using Ni-NTA resin, and it was confirmed using SDS-PAGE and Western blot analyses. Consequently, the Trx-CCL21-pHLIP protein was successfully displayed on the cancer cell surface in a weak acidic microenvironment and showed the same ability as CCL21 in recruiting CCR7-positive cells. Additionally, the CCL21 fusion protein with or without Trx tag showed similar functions. Therefore, the study implies the feasibility of directing a modular genetic method for the development of protein-based drugs.
研究领域:
癌症生物学
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分子生物学
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基因工程
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免疫学
·
蛋白质工程
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DOI
PubMed
高影响因子
Journal of Neuroinflammation
·
2024
·Vol. 21
·期 1
·1-17
·
IF 9.3
Gao Dandan,Zou Bin,Zhu Kunyuan,Bi Shijun,Zhang Wenxu,Yang Xinyu,Lai Jieyu,Liang Guobiao,Pan Pengyu
Background Subarachnoid hemorrhage (SAH) is a severe cerebrovascular disorder primarily caused by the rupture of aneurysm, which results in a high mortality rate and consequently imposes a significant burden on society. The occurrence of SAH initiates an immune response that further exacerbates brain damage. The acute inflammatory reaction subsequent to SAH plays a crucial role in determining the prognosis. Th17 cells, a subset of T cells, are related to the brain injury following SAH, and it is unclear how Th17 cells are cleared in the brain. Meningeal lymphatic vessels are a newly discovered intracranial fluid transport system that has been shown to drain large molecules and immune cells to deep cervical lymph nodes. There is limited understanding of the role of the meningeal lymphatic system in SAH. The objective of this research is to explore the impact and underlying mechanism of drainage Th17 cells by meningeal lymphatics on SAH.Methods Treatments to manipulate meningeal lymphatic function and the CCR7-CCL21 pathway were administered, including laser ablation, injection of VEGF-C geneknockout, and protein injection. Mouse behavior was assessed using the balance beam experiment and the modified Garcia scoring system. Flow cytometry, enzyme-linked immunosorbent assays (ELISA), and immunofluorescence staining were used to study the impact of meningeal lymphatic on SAH drainage. Select patients with unruptured and ruptured aneurysms in our hospital as the control group and the SAH group, with 7 cases in each group. Peripheral blood and cerebrospinal fluid (CSF) samples were assessed by ELISA and flow cytometry.Results Mice with SAH showed substantial behavioral abnormalities and brain damage in which immune cells accumulated in the brain. Laser ablation of the meningeal lymphatic system or knockout of the CCR7 gene leads to Th17 cell aggregation in the meninges, resulting in a decreased neurological function score and increased levels of inflammatory factors. Injection of VEGF-C or CCL21 protein promotes Th17 cell drainage to lymph nodes, an increased neurological function score, and decreased levels of inflammatory factors. Clinical blood and CSF results showed that inflammatory factors in SAH group were significantly increased. The number of Th17 cells in the SAH group was significantly higher than the control group. Clinical results confirmed Th17 cells aggravated the level of neuroinflammation after SAH.Conclusion This study shows that improving the drainage of Th17 cells by meningeal lymphatics via the CCR7-CCL21 pathway can reduce brain damage and improve behavior in the SAH mouse model. This could lead to new treatment options for SAH.
研究领域:
神经科学
·
免疫学
·
脑血管疾病
·
淋巴系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOLOGICAL TRACE ELEMENT RESEARCH
·
2023
·
IF 3.9
Yan Nan,Wang Zhengdong,Li Zhou,Zheng Yang,Chang Nan,Xu Kangjie,Wang Qian,Duan Xiaoxu
This study aimed to examine the immuntoxic effects of arsenic in the nervous system. Our results showed that arsenic increased corticocerebral and hippocampal weights ( p < 0.05). Morris water maze tests revealed that arsenic significantly increased the time spent in latency to platform on the fourth day in 50 mg/L arsenic exposure and the fifth day in 25 and 50 mg/L arsenic exposure, as well as reduced the path length in target quadrant, time spent in target quadrant, and crossing times of the platform ( p < 0.05). Hematoxylin–eosin staining showed that the vacuolated degeneration and pyknosis was found in the cerebral cortex and hippocampus of arsenic-treated mice. The mRNA levels of corticocerebral and hippocampal brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) were decreased in the 50 mg/L arsenic-treated group ( p < 0.05). In addition, immunofluorescence staining showed that 25 and 50 mg/L arsenic all increased the expression of CD11b and glial fibrillary acidic protein (GFAP) in the cerebral cortex and hippocampus ( p < 0.05). Arsenic markedly raised antigen-presenting molecule MHCII and CD40 mRNA levels in the cerebral cortex and hippocampus and upregulated the cell chemokine receptor 5 (CCR5) and CCR7 mRNA levels in the cerebral cortex at the 50 mg/L arsenic group, and increased the CCR7 mRNA levels in the hippocampus at the 25 and 50 mg/L arsenic groups ( p < 0.05). Arsenic activated the nucleotide-binding domain-like receptor protein-3 (NLRP3) inflammasome, and enhanced its upstream promoter NF-κB protein level and downstream regulators IL-18 mRNA levels. Collectively, these results provide new evidences for the neuro-immune toxicity of arsenic. Graphical abstract
研究领域:
神经毒理学
·
免疫毒理学
·
神经科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）