Advanced Healthcare Materials
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2025
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IF 9.6
Jie Zhao,Ming Li,Qiong Wu,Guanzhong Qiao,Hao Jiang,Sheng Zhao,Linhan Zhang,Song Wang,Huijie Jiang
Colorectal cancer (CRC) poses a significant therapeutic challenge due to its immunosuppressive tumor microenvironmentl (TME). In this environment, triggering receptors expressed on myeloid cells 2 (TREM2+) tumor-associated macrophages (TAMs) drive immune evasion and therapy resistance. In this study, CSF1R-IN-3@Mn@MPDA-antiTREM2 (CMMT) is presented, a manganese-doped mesoporous polydopamine nanoplatform conjugated with anti-TREM2 antibodies, which integrates TAM reprogramming and magnetic resonance imaging (MRI)-guided immune monitoring. CMMT has three key characteristics: 1) pH-responsive release of the Colony Stimulating Factor 1 Receptor (CSF1R) inhibitor CSF1R-IN-3 within acidic TME; 2) selective targeting of TREM2+ M2 macrophages, achieving 4.2-fold higher uptake compared to M1 subsets ( P < 0.001); and 3) dual modulation of TREM2 and CSF1R pathways, polarizing M2-TAMs toward pro-inflammatory M1 phenotypes. In orthotopic CRC models, CMMT synergizes with anti-PD-L1 therapy, reducing tumor volume by 72.5% compared to 42.1% for monotherapy ( P < 0.001). It also extends median survival from 28 to 52 days. Importantly, CMMT acts as an MRI contrast agent, with T1 signal intensity correlating with intratumoral TREM2+ macrophage density (r- 0.71, P < 0.05), enabling non-invasive assessment of TME remodeling. This theranostic platform bridges immune modulation and real-time monitoring, providing a promising strategy to overcome immunotherapy resistance in CRC.
研究领域:
肿瘤学
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免疫学
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医学影像学
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产品关联
DOI
PubMed
高影响因子
Journal of Neuroinflammation
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2025
·Vol. 22
·期 1
·1-18
·
IF 10.1
Zhang Lianshuai,Chen Kai,Zeng Ruicheng,Bu Guojun,Chen Xiao-Fen
Background The colony-stimulating factor 1 receptor (CSF1R) is a receptor tyrosine kinase essential for microglial development and homeostasis. While dysregulated CSF1R signaling has been implicated in Alzheimer’s disease (AD), the biological function of its soluble ectodomain (sCSF1R)—generated by a disintegrin and metalloproteinase 17 (ADAM17)-mediated cleavage—remains poorly understood in neurodegeneration. Methods We quantified sCSF1R levels in the brain and cerebrospinal fluid (CSF) of 5×FAD transgenic mice and wild-type controls using ELISA and immunoblotting, and reanalyzed publicly available CSF proteomic datasets from three independent, clinically characterized AD cohorts. Functional studies were performed in primary microglial cultures and through hippocampal delivery of recombinant sCSF1R into 5×FAD mice to evaluate its effects on microglial activity and amyloid pathology. Results In this study, we identify sCSF1R as a previously unrecognized, functionally active modulator of microglial responses in AD. Analysis of three independent clinical cohorts revealed significantly elevated sCSF1R levels in the CSF of AD patients, a finding recapitulated in both the brain and CSF of 5×FAD transgenic mice. Importantly, sCSF1R concentrations showed positive correlations with core AD biomarkers—including total tau, phosphorylated tau, and β-amyloid 1–42 (Aβ42)—and with measures of cognitive performance, highlighting its clinical significance and suggesting that sCSF1R may serve as a marker of disease-associated microglial responses. Functionally, recombinant sCSF1R enhanced microglial survival, migration, proinflammatory signaling, and Aβ phagocytosis in vitro. In vivo, administration of sCSF1R promoted microglial clustering around amyloid plaques, reduced Aβ deposition, and attenuated plaque-associated neuritic dystrophy in 5×FAD mice. Finally, we found that soluble TREM2 (sTREM2)—a CSF biomarker and potent activator of microglia—stimulates ADAM17-dependent cleavage of membrane-bound CSF1R, thereby driving the generation of sCSF1R. Collectively, these findings establish sCSF1R as a novel regulator of microglial function in AD and reveal a regulatory axis linking sTREM2, ADAM17 activity, and CSF1R shedding with potential implications for disease modulation. Conclusions These findings identify sCSF1R as a novel component of the neuroimmune signaling network in AD and highlight its dual potential as a CSF biomarker of beneficial microglial activation and a candidate therapeutic modulator of neuroinflammation and amyloid pathology.
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PubMed
高影响因子
Immunotherapy
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2018
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IF 3.461
Ping Zhang,Songbo Zhao,Chao Wu,Jialu Li,Zixuan Li,Chunmei Wen,Siyi Hu,Gangli An,Huimin Meng,Xingding Zhang,Lin Yang
Tumor immunotherapy has shown great progress for the treatment of cancer; however, both endogenous and exogenous T cells are inhibited by the immunosuppressive tumor microenvironment. Tumor-associated macrophages (TAMs) in the microenvironment play pivotal and complex roles in tumor development and progression. Macrophages are categorized as M1 and M2 types. Relevant studies suggest that M2 TAMs correlate with poor prognosis. Colony-stimulating factor 1 receptor (CSF1R) controls the formation, differentiation and function of M2 macrophages, which helps tumors grow, metastasize and secrete immunosuppressive cytokines. The objectives of this study were to establish two types of third-generation chimeric antigen receptors (CARs) that could specifically target human CSF1R, and to introduce the CARs into NK92MI cells and normal human peripheral blood T cells through lentiviral transduction to produce CAR-natural killer (NK) and -T cells. We then tested their cytotoxicity against cell lines and peripheral blood monocytes expressing CSF1R. In vitro experiments confirmed that third-generation CARs had good target specificity and cytotoxicity. It was expected that CAR-NK and -T cells could specifically kill M2 TAMs in the tumor microenvironment and remove their inhibitory effect. Therefore, CSF1R-targeting CAR-NK and -T cells could represent a novel cellular immunotherapy strategy in conjunction with other antibody-based drugs and targeted therapeutics.
研究领域:
肿瘤学
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免疫学
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细胞治疗
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
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2025
·Vol. 26
·期 9
·3964
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IF 4.9
Xin Li,Zifeng Zhuang,Yuting Hao,Shaozi Lin,Junyan Gu,Shiquan Chang,Lin Lan,Guoping Zhao,Di Zhang
This study investigated the mechanism underlying Paeonol’s therapeutic efficacy against neuropathic pain. GSE158892 dataset data were used to conduct a scRNA-seq analysis. In cell experiments, Schwann cells and macrophages were utilized to examine pain pathogenesis using specific inhibitors. Thirty-two SD rats were randomly divided into four groups: sham, chronic constriction injury (CCI), ibuprofen, and Paeonol. Behavioral tests combined with ELISA, PCR, western blot, immunohistochemistry, and immunofluorescence analyses were conducted. CellChat analysis demonstrated that, following peripheral nerve injury, Schwann cells secreted IL-34, which interacted with CSF1R on macrophages, leading to the infiltration and activation of macrophages. Paeonol reduced IL-34 production by Schwann cells induced with LPS. Conditioned medium from LPS-stimulated Schwann cells treated with Paeonol did not cause macrophage proliferation or migration, activation of the CSF1 pathway, or ROS production. In CCI rats, Paeonol alleviated mechanical and cold hyperalgesia, while reducing the production of serum inflammatory mediators. Additionally, Paeonol decreased the expression levels of IL-34, CSF1R, phosphorylated ERK (p-ERK), phosphorylated NF-κB (p-NF-κB), and components of the NLRP3 inflammasome in the dorsal root ganglia of CCI rats. Conclusion: Alleviation of neuropathic pain by Paeonol treatment may be achieved by inhibiting the IL-34–CSF1R interaction, suppressing Schwann cell–macrophage interactions, and reducing DRG neuroinflammation.
研究领域:
医学
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神经科学
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药理学
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产品关联
DOI
PubMed
高影响因子
Autophagy
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2026
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IF 18.6
Yiping Shi,Long Chen,Yuxiao Feng,Jingtao Liu,Wendi Wu,Yawei Jin,Huan Tong,Yijie Huang,Yiming Li,Zhaokuan Li,Guo Zhou,Ben He,Yu Wang,Qin Shao
Doxorubicin is a widely used chemotherapeutic agent, but its clinical application is hindered by severe cardiotoxicity. Among immune cells, Cx3cr1+ macrophages have emerged as key regulators of cardiovascular disease, with their development and maturation tightly controlled by CSF1R (colony stimulating factor 1 receptor). Using multi-omics sequencing, we observed a marked expansion of Cx3cr1+ macrophages in doxorubicin-induced cardiomyopathy, yet their precise functional role in this pathological process has remained elusive. This study employed various genetically modified mouse models, including cell depletion models, lineage tracing models, and conditional gene knockout models targeting Cx3cr1+ macrophages, alongside transcriptomic sequencing, proteomic profiling, and multi-level in vivo and in vitro experiments to elucidate the role and mechanisms of Cx3cr1+ macrophages and their receptor CSF1R in doxorubicin-induced cardiac injury. We found that Cx3cr1+ macrophages are significantly enriched in hearts affected by doxorubicin-induced cardiomyopathy, and their depletion notably improves cardiac function. Further investigation revealed that in these macrophages, CSF1R competitively binds to the E3 ubiquitin ligase NEDD4, thereby inhibiting the ubiquitination and degradation of PARP1. This process promotes inflammasome activation and pyroptosis, driving massive IL1B secretion. IL1B directly suppresses cardiomyocyte mitophagy, disrupts energy metabolic homeostasis, and ultimately leads to cardiac dysfunction. Notably, the use of the CSF1R inhibitor PLX3397 or an IL1B-neutralizing antibody effectively halted these pathological processes and significantly improved cardiac function. In summary, this study unveils a novel mechanism through which Cx3cr1+ macrophages regulate cardiomyocyte function via the CSF1R-PARP1-IL1B-mitophagy signaling axis, providing a new theoretical foundation and intervention strategy for doxorubicin-induced cardiomyopathy targeted therapy.Abbreviations: BMDM: bone marrow-derived macrophages; CKMB: creatine kinase MB isoenzyme; CSF1R: colony stimulating factor 1 receptor; csf1r-cKO: csf1r conditional knockout; DIC: doxorubicin-induced cardiomyopathy; DOX: doxorubicin; HE: hematoxylin and eosin; HW:TL: heart weight:tibial length; LDH: lactate dehydrogenase; MAP1LC3/LC3: microtuble-associated protein 1 light chain 3; NPPA: natriuretic peptide type A; PI: propidium iodide; PYCARD/ASC: PYD and CARD domain containing; TNNT2/cTnT: troponin T2, cardiac; WGA: wheat germ agglutinin.
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DOI
高影响因子
Journal of Inflammation Research
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2021
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IF 6.922
Qianxue Mou,Ke Yao,Meng Ye,Bowen Zhao,Yuanyuan Hu,Xiaotong Lou,Huixia Li,Hong Zhang,Yin Zhao
Purpose Optic nerve injury (ONI) causes neuroinflammation and neurodegeneration leading to visual deficits. The response of microglia has emerged as an impactful component of etiology in neurodegeneration. This study aimed to investigate the effect of SIRT1-mTORC1 signaling pathway in microglia regulation after ONI. Methods Cx3Cr1-Cre ERT2 / Raptor F/F and Cx3Cr1-Cre ERT2 / Sirt1 F/F mice were used to delete Raptor and Sirt1 in microglia, respectively. Optic nerve crush (ONC) model was established to mimic ONI. PLX5622, a highly specific inhibitor of the colony-stimulating factor 1 receptor (CSF1R), is used to eliminate microglia in optic nerve. Ionized calcium binding adaptor molecule 1 (Iba1) immunostaining was used to detect microglial activation. Retinal ganglion cells (RGCs) were quantified by Nissl staining and retinal whole-mount immunostaining with RNA-binding protein with multiple splicing (RBPMS). Axonal damage was valued by transmission electron microscopy (TEM). Results Microglial activation emerged on day 3 post ONC and was earlier than RGCs loss which occurred at day 5 after injury. Depleting microglia with PLX5622 could attenuate the loss of RGCs and axon damage after ONC. Gain- and loss-of-function studies revealed that SIRT1 determined the activation of microglia in optic nerve. In addition, microglia-specific deletion of Raptor resulted in decreased microglial activation. Interestingly, activating mTORC1 with CCT007093 could reverse the function of SIRT1 in regulating the process of microglial activation mediated RGCs loss. Conclusion Our study reveals a potential novel mechanism of SIRT1-mTORC1 pathway in microglia regulation, and indicates a therapeutic potential for the protection of RGCs in ONI.
研究领域:
神经科学
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眼科学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Bioactive Materials
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2022
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IF 16.874
Yuehua Wang,Zhenjie Wang,Fei Jia,Qing Xu,Zhilin Shu,Junlin Deng,Aimin Li,Meng Yu,Zhiqiang Yu
Clinical sorafenib treatment could activate C-X-C receptor type 4 (CXCR4)/stromal source factor-1α (SDF-1α) axis to aggravate intra-tumoral hypoxia of hepatocellular carcinoma (HCC), which further leads to progression, invasion, metastasis, and immunosuppression of tumors and in return causes resistance to sorafenib therapy. Therefore, a multi-functional oxygen delivery nanoplatform was rationally constructed based on an oxygen-saturated perfluorohexane (PFH)-cored liposome, with the CXCR4 antagonist LFC131 peptides modifying on the surface to simultaneously deliver sorafenib and the CSF1/CSF1R inhibitor PLX3397 (named [email protected] ) for sorafenib-resistant HCC treatment. The [email protected] was developed to overcome sorafenib resistance by synergistic effects of the following 3 roles: 1) the O 2 -saturated PFH core could alleviate the tumor hypoxia by O 2 supply; 2) the LFC131 peptide recognized the hypoxia-related overexpressed CXCR4 and then blocked SDF-1α/CXCR4 axis to re-sensitize the HCC cells to sorafenib; 3) PLX3397 activated the immune responses via inhibiting the CSF1/CSF1R pathway in TAMs, further enhanced CD8 + T cell infiltration to reverse immunosuppression in tumors. Antitumor performance on H22 tumor-bearing mice and HCC patient-derived tumor xenograft (PDX) model showed that [email protected] could overcome sorafenib resistance by synergistic effect of hypoxia attenuation, resistance-related gene regulation, and immune-microenvironment modification.
研究领域:
药理学
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肿瘤学
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纳米技术
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免疫疗法
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产品关联
DOI
PubMed
高影响因子
Proteomics Clinical Applications
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2022
·Vol. 16
·期 6
·2100099
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IF 3.603
Ting Li,Hong Qu,Haibo Ding,Haiteng Deng,Yuling Chen
Purpose Antiretroviral therapy (ART) prevents human immunodeficiency virus (HIV)-1 onward transmission and disease progression, leading to excellent prognosis in people living with HIV-1 (PWH). However, side effects, complications, and impaired immune reconstitution persist in some patients treated with ART. We aimed to profile proteome changes in plasma before and after ART to identify the molecular pathways altered by ART. Experimental Design Quantitative proteomics analysis based on tandem mass tag (TMT) labeling was used to profile proteome changes of paired plasma samples from HIV-1 patients before receiving ART and after ART treatment. Results A total of 1398 protein groups (PGs) were identified, in which 18 proteins were downregulated and 50 were upregulated in plasma from ART treated patients. Based on Ingenuity Pathway analysis (IPA), gap junction signaling and actin cytoskeleton signaling were enriched among upregulated proteins, while downregulated proteins were mainly participated in IL-15 signaling pathway. Patients with the low level of CSF1R and the high levels of MINPP1 and TGM3 showed better CD4 + T-cell recovery. Conclusions The present study provided plasma proteome changes after ART to elucidate the underlying mechanistic pathways in response to ART, and also identified potential targets to prompt immune reconstitution.
研究领域:
免疫学
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蛋白质组学
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病毒学
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临床研究
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产品关联
DOI
PubMed
高影响因子
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