ADVANCED MATERIALS
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2024
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IF 27.4
Zhiyan Li,Xianghui Li,Yanjun Lu,Xudong Zhu,Wenxuan Zheng,Kai Chen,Xingzhou Wang,Tao Wang,Wenxian Guan,Zhi Su,Song Liu,Jinhui Wu
Immunotherapy has emerged as a highly effective therapeutic strategy for cancer treatment. Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon gene (STING) pathway activation facilitates tumor-associated macrophage (TAM) polarization toward M1 phenotype, and Mn 2+ are effective agents for this pathway activation. However, the high in vivo degradation rate and toxicity of Mn 2+ hamper clinical application of immunotherapy. Here, this work has newly synthesized and screened manganese porphyrins for Mn 2+ transport, referred to as photo-STING agonists (PSAs), and further encapsulate them into core-shell nanoparticles named Rm@PP-GA with dual specificity for tumor tissue and TAMs. Not only do PSAs achieve higher Mn 2+ delivery efficiency compared to Mn 2+ , but they also generate reactive oxygen species under light exposure, promoting mitochondrial DNA release for cGAS-STING pathway activation. In Rm@PP-GA, globin and red blood cell membranes (Rm) are used for erythrocyte efferocytosis-mimicking delivery. Rm can effectively prolong the in vivo circulation period while globin enables PSAs to be taken up by TAMs via CD163 receptors. After Rm rupture mediated by perfluorohexane in nanoparticles under ultrasonication, drugs are specifically released for TAM repolarization. Further, dendritic cells mature, as well as T lymphocyte infiltrate, both of which favor tumor eradication. Therefore, cancer immunotherapy is optimized by novel PSAs delivered by erythrocyte efferocytosis-mimicking delivery pattern.
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PHARMACOLOGICAL RESEARCH
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2024
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IF 9.1
Xiaozhi Hu,Yanyang Nan,Yuting Zhang,Jiajun Fan,Hanqi Wang,Yu Bai,Yuanzhen Zhang,Xuyao Zhang,Zeguo Zhu,Zhonglian Cao,Xiaomiao Ye,Tao Wu,Shuwen Xu,Zhengyu Wu,Wei Hu,Dianwen Ju
Atherosclerosis (AS) ultimately cause major adverse cardiovascular events (MACEs). While traditional strategies by lipid-reducing have reduced MACEs, many patients continue to face significant risks. It might attribute to the upregulation of CD47 expression in AS lesions, that mediated anti-efferocytosis of macrophages. Therefore, we propose simultaneously blocking ANGPTL3, a vital regulator of lipid metabolism, and CD47 might be a potential approach for AS therapy. Firstly, we investigate the role of a novel anti-ANGPTL3 nanobody-Fc (FD03) in AS. We found that FD03 treatment significantly decreased circulating lipids, plaque size, and lipid deposition in apoE -/- mice compared to control Ab, but there was a twofold increase in plaque formation in comparison to baseline. However, immunofluorescence indicated the upregulation of CD47 expression in the plaques even after FD03 treatment compared to normal vascular tissue. Next, a bifunctional protein containing signal regulatory protein alpha (SIRPα) and FD03 (SIRPαD1-FD03) was constructed to block CD47 and ANGPTL3 concurrently, which had high purity, robust stability, and high affinity to CD47 and ANGPTL3 with biological activity in vitro . Furthermore, SIRPαD1-FD03 fusion protein exhibited the enhanced therapeutic effect on AS compared with SIRPαD1-Fc or FD03, regressing plaque contents and the necrotic core equal to baseline. Mechanistically, SIRPαD1-FD03 reduced serum lipids, augmented the efferocytosis rate and macrophage M2 polarization, and decreased the reactive oxygen species (ROS) and lipid peroxidation level in atherosclerotic plaques. Collectively, our project suggests an effective approach for AS by simultaneously blocking ANGPTL3 and CD47 to regulate lipid metabolism, macrophage activity and lipid peroxidation.
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NEUROSCIENCE
·
2026
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IF 3.3
Xiaoyu Lin,Wanliang Du,Ruile Fang,Ying Ma,Yongjun Wang,Jialei Yang
Systemic inflammation worsens ischemic stroke by increasing brain injury, neurological deficits, and neuroinflammation. • Systemic inflammation enhances microglial NF-κB activity and promotes p65/β-catenin interaction. • Systemic inflammation downregulates microglial Wnt/β-catenin/CD36 axis and impairs microglial efferocytosis. • Lithium chloride restores Wnt/β-catenin signaling and microglial efferocytosis, improving stroke outcome under systemic inflammation. Systemic inflammation is associated with worse outcomes after ischemic stroke, but the underlying mechanisms remain poorly understood. Microglial efferocytosis limits post-stroke inflammation and promotes recovery, whereas Wnt/β-catenin signaling has been implicated in neuroprotection and in regulation of CD36, a key efferocytotic receptor. Here, we investigated whether systemic inflammation is associated with alterations in microglial Wnt/β-catenin/CD36 axis and efferocytosis during ischemic injury. Mice were pretreated with lipopolysaccharide (LPS) before transient middle cerebral artery occlusion/reperfusion (tMCAO/R), and BV2 microglia were exposed to LPS before oxygen-glucose deprivation/reoxygenation (OGD/R). LPS pretreatment markedly increased infarct volume, worsened neurological deficits, and amplified post-ischemic neuroinflammatory responses. These effects were accompanied by enhanced microglial NF-κB signaling, increased p65/β-catenin interaction, and reduced nuclear β-catenin, consistent with suppression of Wnt/β-catenin signaling. Reduced CD36 expression and impaired microglial efferocytosis were observed in parallel. Notably, pharmacological activation of Wnt/β-catenin signaling with lithium chloride (LiCl) restored CD36 expression and microglial efferocytosis under LPS-pretreated conditions, and was accompanied by smaller infarcts, improved neurological function, and attenuated neuroinflammation. Collectively, these findings show that LPS pretreatment exacerbates ischemic stroke and is associated with enhanced microglial NF-κB signaling, dysregulation of the Wnt/β-catenin/CD36 axis, and impaired microglial efferocytosis. These results support defective microglial efferocytosis as a potential biological link between systemic inflammation and aggravated ischemic injury and identify Wnt/β-catenin signaling as a candidate pathway for further therapeutic investigation Download: Download high-res image (128KB) Download: Download full-size image
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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
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高影响因子
Cell Communication and Signaling
·
2023
·Vol. 21
·期 1
·1-18
·
IF 8.4
Liao Zhaohong,Lan Haiqiang,Jian Xiaoting,Huang Jingwen,Wang Han,Hu Jijie,Liao Hua
Background To explore the role of skeletal muscle specific TGF-β signaling on macrophages efferocytosis in inflamed muscle caused by Cardiotoxin (CTX) injection. Methods CTX myoinjury was manipulated in TGF-βr2 flox/flox (control) mice or transgenic mice with TGF-β receptor 2 (TGF-βr2) being specifically deleted in skeletal muscle (SM TGF-βr2 −/− ). Gene levels of TGF-β signal molecules, special inflammatory mediators in damaged muscle or in cultured and differentiated myogenic precursor cells (MPC-myotubes) were monitored by transcriptome microarray or qRT-PCR. TGF-β pathway molecules, myokines and embryonic myosin heavy chain in regenerating myofibers, the phenotype and efferocytosis of macrophages were evaluated by immunofluorescence, immunoblotting, Luminex, or FACS analysis. In vitro apoptotic cells were prepared by UV-irradiation. Results In control mice, TGF-β-Smad2/3 signaling were significantly up-regulated in regenerating centronuclear myofibers after CTX-myoinjury. More severe muscle inflammation was caused by the deficiency of muscle TGF-β signaling, with the increased number of M1, but the decreased number of M2 macrophages. Notably, the deficiency of TGF-β signaling in myofibers dramatically affected on the ability of macrophages to conduct efferocytosis, marked by the decreased number of Annexin-V − F4/80 + Tunel + macrophages in inflamed muscle, and the impaired uptake of macrophages to PKH67 + apoptotic cells transferred into damaged muscle. Further, our study suggested that, the intrinsic TGF-β signaling directed IL-10-Vav1-Rac1 efferocytosis signaling in muscle macrophages. Conclusions Our data demonstrate that muscle inflammation can be suppressed potentially by activating the intrinsic TGF-β signaling in myofibers to promote IL-10 dependent-macrophages efferocytosis.
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CHEMICAL ENGINEERING JOURNAL
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2024
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IF 13.3
Wenqian Zhang,Shengming Zhang,Samuel Knoedler,Wenhao Han,Kangkang Zha,Hui Li,Adriana Christine Panayi,Michael Alfertshofer,Bong-Sung Kim,Weixian Hu,Yanzhi Zhao,Qian Feng,Yuval Rinkevich,Bobin Mi,Guohui Liu
Efferocytosis is a critical process whereby macrophages residing in the wound area play a key role in the efficient clearing and degradation of apoptotic neutrophils. This process is followed by a phenotypic transition toward an anti-inflammatory state, essential for inflammation resolution and tissue repair. The cystine/glutamate antiporter SLC7A11 has recently been identified as an inhibitor of efferocytosis, and its blockade has been found to enhance wound healing. In this study, we demonstrated that tiliroside, a plant-derived glycoside containing flavones, binds directly to SLC7A11 and pyruvate kinase isozyme M2 (PKM2). This was established by molecular docking predictions and activity-based protein profiling (ABPP). Cytological experiments revealed that tiliroside promoted the process of efferocytosis and led to glycolysis-related macrophage reprogramming. To facilitate targeted drug delivery to macrophages at diabetic wound sites, we designed a novel hybrid biomaterial. This hybrid biomaterial, prepared as Gel@Til iRGD&PS@PLGA NPs is manufactured by loading tiliroside (Til)-conjugated iRGD&PS double modified lipid nanoparticles (iRGD&PS@PLGA NPs) into a pH-responsive hydrogel matrix. The administration of Gel@Til iRGD&PS@PLGA NPs in diabetic cutaneous wound models has been shown to significantly promote tissue regeneration through the promotion of efferocytosis and glycolysis-related macrophage reprogramming. Therefore, this study introduces a novel approach to diabetic wound management by leveraging the promotion of efferocytosis.
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