Science Advances
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2024
·Vol. 10
·期 40
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IF 11.7
Naming Wu,Jun Li,Lu Li,Liu Yang,Liyun Dong,Chen Shen,Shanshan Sha,Yangxue Fu,Enzhu Dong,Fang Zheng,Zheng Tan,Juan Tao
Despite our increasing understanding of macrophage heterogeneity, drivers of macrophage phenotypic and functional polarization in the microenvironment are not fully elucidated. Here, our single-cell RNA sequencing data identify a subpopulation of macrophages expressing high levels of the phagocytic receptor MER proto-oncogene tyrosine kinase (MerTK+ macrophages), which is closely associated with melanoma progression and immunotherapy resistance. Adoptive transfer of the MerTK+ macrophages into recipient mice notably accelerated tumor growth regardless of macrophage depletion. Mechanistic studies further revealed that ALK And LTK Ligand 1 (ALKAL1), a target gene of aryl hydrocarbon receptor (AhR), facilitated MerTK phosphorylation, resulting in heightened phagocytic activity of MerTK+ macrophages and their subsequent polarization toward an immunosuppressive phenotype. Specifically targeted delivery of AhR antagonist to tumor-associated macrophages with mannosylated micelles could suppress MerTK expression and improved the therapeutic efficacy of anti–programmed cell death ligand 1 therapy. Our findings shed light on the regulatory mechanism of MerTK+ macrophages and provide strategies for improving the efficacy of melanoma immunotherapy.
研究领域:
免疫学
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肿瘤学
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分子生物学
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DOI
PubMed
高影响因子
STEM CELLS
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2023
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IF 5.2
Li Zhi-hui,Chen Jun-feng,Zhang Jing,Lei Zi-ying,Wu Li-li,Meng Shi-bo,Wang Jia-lei,Xiong Jing,Lin Deng-na,Wang Jun-yi,Gao Zhi-liang,Lin Bing-liang
Acute-on-chronic liver failure (ACLF) is a severe disease with a high mortality. Macrophage-related inflammation plays a crucial role in ACLF development. Mesenchymal stem cells (MSCs) treatment was demonstrated to be beneficial in ACLF in our previous study; however, the underlying mechanisms remain unknown. Therefore, mouse bone marrow-derived MSCs were used to treat an ACLF mouse model or cocultured with RAW264.7/J774A.1 macrophages that were stimulated with LPS. Histological and serological parameters and survival were analyzed to evaluate efficacy. We detected changes of Mer tyrosine kinase (Mertk), JAK1/STAT6, inflammatory cytokines, and markers of macrophage polarization in vitro and in vivo. In ACLF mice, MSCs improved liver function and 48-h survival of ACLF mice and alleviated inflammatory injury by promoting M2 macrophage polarization and elevated Mertk expression levels in macrophages. This is significant, as Mertk regulates M2 macrophage polarization via the JAK1/STAT6 signaling pathway.
研究领域:
肝病学
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免疫学
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干细胞生物学
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细胞信号传导
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DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
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2026
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IF 2.5
Chunhui Shan,Qi Bing,Gang Qiu,Hui Zhang,Yingmin Chen
Galectin-3 disrupts microglial P2X7R/MerTK balance after stroke • ERK/ROS/BRD4 axis mediates Gal-3-induced P2X7R upregulation • Gal-3 promotes cGAS-STING inflammation and apoptosis via HIF1α/P2X7R • TD-139 restores P2X7R/MerTK balance and reduces cerebral infarction • Targeting Gal-3 improves motor, cognitive, and grip strength in MCAO rats This study demonstrates that Galectin-3 (Gal3) exacerbates cerebral infarction progression by modulating the P2X7R/MerTK equilibrium in microglia via the ERK/BRD4/HIF1α signaling axis, with reactive oxygen species (ROS) serving as a potential intermediate mediator linking ERK activation to BRD4 upregulation based on prior literature evidence. Single-cell transcriptomic analysis revealed that ischemia drives microglia from a homeostatic state to an activated disease phenotype, and virtual Gal3 knockout predicted corresponding downregulation of BRD4. Using a rat model of cerebral infarction, we found that the Gal3 inhibitor TD-139 significantly reduced infarct volume, promoted M2 polarization of microglia, and improved neurological function in behavioral assays. Mechanistic investigations in BV2 microglia revealed that Gal3 activates ERK1/2, leading to ROS accumulation, BRD4 upregulation, and subsequent HIF1α-mediated P2X7R transcription, while suppressing KLF4 and MerTK. This cascade increased P2X7R expression and suppressed MerTK/KLF4 expression, generating a pro-inflammatory and pro-apoptotic microenvironment. Notably, pharmacological inhibition of Gal3 enhanced efferocytosis and reduced apoptosis, whereas P2X7R blockade exerted similar neuroprotective effects. These findings identify Gal3 as a key regulator of microglial polarization via the experimentally validated ERK/BRD4/HIF1α-P2X7R signaling cascade, where P2X7R activation concurrently triggers cGAS-STING-mediated pro-inflammatory/pyroptotic responses and suppresses the KLF4/MerTK efferocytosis axis. Targeting this regulatory network could provide therapeutic benefits in cerebral infarction by shifting microglia toward the neuroprotective M2 phenotype and facilitating inflammation resolution. Targeting this pathway could provide therapeutic benefits in cerebral infarction by shifting microglia toward the neuroprotective M2 phenotype and facilitating inflammation resolution. Data were analysed using one-way ANOVA followed by Tukey's post-hoc test for multiple comparisons; P < 0.05 was considered statistically significant.
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DOI
高影响因子
Advanced Healthcare Materials
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2024
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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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DOI
PubMed
高影响因子
MATERIALS & DESIGN
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2023
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IF 8.4
Peidong You,Anning Yang,Yue Sun,Hongwen Zhang,Yaling Zeng,Yinju Hao,Jiantuan Xiong,Shengchao Ma,Huiping Zhang,Bin Liu,Yideng Jiang
Atherosclerosis is chronic inflammatory disease tightly related with defective efferocytosis of apoptotic cells (ACs) in the plaques. The strategy of efferocytosis reactivation using Atorvastatin (AT) and Metformin (Met) has attracted increasing attention for atherosclerosis treatment. Although these drug-based therapies could stimulate the phagocytic clearance of ACs, the rapid drug clearance and poor bioavailability limited their efficacy. In this study, by co-loading AT and Met into poly(lactic-co-glycolic) acid nanoparticles (PLGA NPs), we developed a biomimetic nanocomplexes for targeted atherosclerosis treatment. Macrophages membrane-coated nanocomplexes efficiently avoided the clearance of NPs from immune system and achieved targeting ability to the atherosclerotic plaques. Moreover, modified hyaluronic acid (HA) delivered NPs into the dysfunctional efferocytic cells of plaques, and achieved the plaques-macrophages-targeted therapy. In vitro results indicated that the biomimetic nanocomplexes reactivated efferocytosis by facilitating macrophages polarization from M1 to M2 phenotype through enhancing ERK5/MerTK pathway and inhibiting cellular senescence through inhibiting p53-p16/pRB pathway. In vivo study indicated that this biomimetic nanocomplexes accumulated in the atherosclerotic plaques, resulting in reduction of necrotic core area and protection against plaque rupture by reactivating efferocytosis. These findings indicated that reactivation of efferocytosis by AT and Met co-delivered nanocomplexes provided a novel promising strategy for targeted atherosclerosis treatment.
研究领域:
心血管疾病
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纳米技术
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药学
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生物医学工程
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DOI
高影响因子
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