Journal for ImmunoTherapy of Cancer
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2022
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IF 12.469
Dandan Sheng,Wei Ma,Rui Zhang,Lei Zhou,Qiaodan Deng,Juchuanli Tu,Weilong Chen,Fuchuang Zhang,Nailong Gao,Mengxue Dong,Dong Wang,Fengkai Li,Yin Liu,Xueyan He,Shengzhong Duan,Lixing Zhang,Tong Liu,Suling Liu
Background Although the antitumor efficacy of docetaxel (DTX) has long been attributed to the antimitotic activities, its impact on the tumor microenvironment (TME) has recently gained more attention. Macrophages are a major component of the TME and play a critical role in DTX efficacy; however, the underlying action mechanisms remain unclear. Methods DTX chemotherapeutic efficacy was demonstrated via both macrophage depletion and C–C motif chemokine ligand 3 (Ccl3)-knockout transgenic allograft mouse model. Ccl3-knockdown and Ccl3-overexpressing breast cancer cell allografts were used for the in vivo study. Combination therapy was used to evaluate the effect of Ccl3 induction on DTX chemosensitivity. Vital regulatory molecules and pathways were identified using RNA sequencing. Macrophage phagocytosis of cancer cells and its influence on cancer cell proliferation under DTX treatment were assessed using an in vitro coculture assay. Serum and tumor samples from patients with breast cancer were used to demonstrate the clinical relevance of our study. Results Our study revealed that Ccl3 induced by DTX in macrophages and cancer cells was indispensable for the chemotherapeutic efficacy of DTX. DTX-induced Ccl3 promoted proinflammatory macrophage polarization and subsequently facilitated phagocytosis of breast cancer cells and cancer stem cells. Ccl3 overexpression in cancer cells promoted proinflammatory macrophage polarization to suppress tumor progression and increase DTX chemosensitivity. Mechanistically, DTX induced Ccl3 by relieving the inhibition of cAMP-response element binding protein on Ccl3 via reactive oxygen species accumulation, and Ccl3 then promoted proinflammatory macrophage polarization via activation of the Ccl3–C-C motif chemokine receptor 5–p38/interferon regulatory factor 5 pathway. High CCL3 expression predicted better prognosis, and high CCL3 induction revealed better DTX chemosensitivity in patients with breast cancer. Furthermore, both the Creb inhibitor and recombinant mouse Ccl3 significantly enhanced DTX chemosensitivity. Conclusions Our results indicate that Ccl3 induced by DTX triggers proinflammatory macrophage polarization and subsequently facilitates phagocytosis of cancer cells. Ccl3 induction in combination with DTX may provide a promising therapeutic rationale for increasing DTX chemosensitivity in breast cancer.
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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分子生物学
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DOI
PubMed
高影响因子
VETERINARY RESEARCH
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2026
·Vol. 57
·期 1
·175
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IF 3.8
Jiang Luyao,Yang Fan,Wu Jiayan,Li Zhengliang,Zhu Xiemin,Pan Hao,Zhang Shaotong,Pan Haochun,Wang Hang,Yao Jingting,Yan Ping,Gao Qingqing,Huan Changchao,Gao Song,Jiao Xinan,Liu Xiufan
Host defense peptides (HDPs) possess both direct bacteriocidal and immunomodulatory activities. In this study, chicken cathelicidin-1 (cCATH-1) and chicken cathelicidin-3 (cCATH-3) were selected based on their markedly different minimum inhibitory concentrations (MICs) against avian pathogenic Escherichia coli (APEC) strains, with MICs of cCATH-1 being 4- to 16-fold lower than those of cCATH-3. However, following intraperitoneal challenge with APEC strain E058 (4 × 10⁶ CFU/mouse), 80% of cCATH-3 treated mice survived while 20% of cCATH-1 treated mice survived. Flow cytometry (FC) revealed significantly lower peripheral blood Ly6C high monocytes but higher peritoneal Ly6C high macrophages in cCATH-3-treated mice at 4 and 8 h post-treatment. Peritoneal CCL3 secretion was significantly upregulated in cCATH-3 treated mice at 8 h post-treatment. Upon knockout of macrophages, the protection of cCATH-3 in mice against APEC E058 challenge was markedly abolished. In vitro, peritoneal macrophages treated with cCATH-3 showed stronger bacteriocidal activity than those treated with cCATH-1. Mouse CCL-3 (mCCL3)-specific antibody neutralize the effect of mCCL3 on macrophages chemotaxis in vitro. mCCL3-specific antibody administration resulted in 0% survival in cCATH-3-treated mice versus 60% survival in cCATH-3-treated mice administered with mock antibody, while cCATH-1-treated mice showed 0% survival administered with either mCCL3-specific antibody or mock antibody after APEC E058 strain challenge. In summary, cCATH-3 provides robust protection against APEC infection compared with cCATH-1 in mice, partially through CCL3-mediated macrophage chemotaxis and enhanced bacteriocidal activity in activated macrophages, revealing a novel mechanism of avian cathelicidins and supporting HDPs as alternatives to antibiotics for controlling avian colibacillosis.
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DOI
高影响因子
Immunity & Ageing
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2026
·Vol. 23
·期 1
·12
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IF 8.3
Sun Ruiqing,Luo Lan,Chen Yang,Sun Liangjie,Huo Yuhao,Ding Chong,Wang Yixiang
Background Senile osteoporosis (SOP) is becoming a critical public health burden particularly in aging societies due to escalating fracture susceptibility among elderly populations. Despite advances in SOP research, the mechanistic role of immune cell alterations in senile osteoporosis remains unclear. Methods As a validated SOP model, senescence-accelerated mouse prone 6 (SAMP6) mice were used for mechanistic studies, comparing with age- and gender-matched controls-senescence-accelerated mouse resistant 1 (SAMR1) mice. We combined micro-CT, molecular biology and histological techniques to assess the bone mineral density in femurs. To investigate dynamic interactions and differential pathways of immune cells within the bone marrow microenvironment, we employed a multi-omics integration strategy including single-cell RNA sequencing, transcriptome sequencing and flow cytometry. Furthermore, we conducted multicolor immunofluorescence and multiplex cytokine analysis to verify the above results. Moreover, we utilized BaF3 and RAW 264.7 cell lines to study the cell interactions during osteoclastogenesis and BX471(a CCR1 antagonist) was used to block this process. Results SAMP6 mice showed a marked decline in bone mass accompanied by elevated reactive oxygen species (ROS) level in 3-month-old. The single-cell RNA sequencing of bone marrow revealed that a prominent depletion of B lymphocytes, with pro-B cells exhibiting the most pronounced reduction. Multi-omics integration analysis of pro-B cells suggested a significant activation of the Fos/Jun (AP-1) transcription complex accompanied by upregulation of chemokine CCL3 in the SAMP6 group. In vitro assays showed that H 2 O 2 -induced oxidative stress in BaF3 cells triggers Fos/Ccl3 axis activation and promoted osteoclastogenesis in RAW 264.7 cells. Moreover, blocking CCR1 with BX471 could suppress this effect. Conclusions Our findings suggest that the elevation of ROS levels within bone marrow microenvironment accelerates immune-senescence of B lymphocytes, characterized by a significant reduction in progenitor B-cell populations, which subsequently activates the Fos/Jun-mediated stress signaling pathway. The cascade ultimately results in the overexpression of CCL3, further promoting osteoclastogenesis of macrophage through CCL3-CCR1 axis. CCR1 antagonist could alleviate pro-inflammatory osteoclast formation, revealing a potential therapeutic target for senile osteoporosis.
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DOI
PubMed
高影响因子
Pharmacology Research & Perspectives
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2020
·Vol. 8
·期 5
·e00660
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IF 2.052
Jingyi Zhao,Ying Chen,Lijun Dong,Xin Li,Ruijie Dong,Dongmei Zhou,Chengzhi Wang,Xiangdong Guo,Jieyou Zhang,Zhenyi Xue,Qing Xi,Lijuan Zhang,Guangze Yang,Yan Li,Rongxin Zhang
Acute peritonitis is an acute inflammatory response of the peritoneal cavity to physical injury and chemical stimulation. Timely resolution of this response is critical to prevent further damage to the body, which can eventually lead to more severe chronic inflammation. Arctigenin (ATG) is the main active ingredient of the Chinese medicine Arctium lappa . In recent years, there have been an increasing number of studies on the anti-inflammatory effect of ATG, but there have been few studies on the effect of ATG on acute inflammation, especially in acute peritonitis, which has not been reported. In this study, a mouse model of experimental acute peritonitis induced by thioglycolate (TG) solution was used to study the protective anti-inflammatory effect of ATG against acute peritonitis and the relevant mechanism. Our results showed that, after 12 hours of TG treatment, ATG significantly reduced inflammatory cell infiltration in mouse tissues and inhibited the secretion and expression of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) in mice. ATG significantly reduced the percentage of CD11b + Ly6G + neutrophils and F4/80 + macrophages in the spleen and peritoneal exudate. In addition, ATG significantly inhibited the expression of the chemokines CCL3 and CCL4 and the adhesion molecule CD62L on the surface of CD11b-positive monocytes. ATG was observed to inhibit the phosphorylation of p65 and p38 in LPS-stimulated RAW264.7 cells. In conclusion, ATG can improve the symptoms of TG-induced acute peritonitis through immune regulation. ATG can reduce the inflammatory response in TG-induced acute peritonitis in mice.
研究领域:
药理学
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免疫学
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炎症性疾病
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2024
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IF 4.8
Shu-Zhen Dai,Ri-Hong Wu,Hengyu Chen,Ming-Hui Chen,Weijing Xie,Wu-Ping Zheng,Guang-Hong Tan,Feng-Ying Huang
Background The process of NETosis is observed in a range of inflammatory conditions. Progesterone (P4) has been shown to alleviate inflammation caused by viral infections such as influenza and SARS-CoV-2. However, the precise molecular mechanisms responsible for this effect are not yet fully understood. Therefore, the present investigation aims to explore whether P4 can exert its anti-inflammatory properties by inhibiting NETosis and the related molecular pathways. Methods Airway inflammation caused by rhinovirus serotype-1b (RV-1b) was induced in male BALB/c mice. The inflammation was assessed through histological examination and calculation of inflammatory cells present in the bronchoalveolar lavage fluid. Flow cytometry was used to analyze the inflammatory cells and NETotic neutrophils. Western blotting analysis was conducted to detect proteins associated with NETosis, inflammasome activation, and signaling. Furthermore, confocal microscopy was utilized to observe neutrophil extracellular trap (NET) structures in vivo tissues and in vitro neutrophils, neutrophil infiltration, and inflammasome formation. Results The administration of P4 proved to be an effective treatment for reducing airway inflammation and the production of NETs caused by RV-1b infection. The infection triggered the activation of NLRP3 inflammasomes in neutrophils, which led to the maturation of IL-1β and subsequent activation of both the NF-κB and p38 signaling pathways. The activation of NF-κB signaling resulted in the secretion of downstream chemokines CCL3 and IL-6, which led to an increase in neutrophil infiltration into the lung airways. Moreover, the activation of p38 signaling led to the generation of reactive oxygen species, resulting in NETosis. However, the administration of P4 inhibited the activation of the NLRP3 inflammasome, which subsequently led to the deactivation of both the IL-1β-NF-κB and IL-1β-p38 axes. As a result, there was a reduction in neutrophil infiltration and NETosis. Furthermore, TGF-β-activated kinase 1 (TAK1) was identified as an intermediary enzyme. P4 inhibits both the NF-κB and IL-1β-p38 pathways by suppressing the activity of TAK1. Conclusion The capacity of P4 to mitigate rhinovirus-induced airway inflammation is attributed to its ability to impede the infiltration of neutrophils and NETosis. As inflammation mediated by NETosis is widespread in diverse disorders, our findings propose that P4 could potentially function as a universal therapeutic agent in the management of such ailments.
研究领域:
免疫学
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呼吸病学
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病毒学
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药理学
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产品关联
DOI
PubMed
高影响因子
ADVANCED MATERIALS
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2024
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IF 27.4
Qingshuang Zou,Ke Liao,Guangchao Li,Xin Huang,Yongwei Zheng,Gun Yang,Min Luo,Evelyn Y. Xue,Chuanqing Lan,Shuai Wang,Yao Shen,Dixian Luo,Dennis K. P. Ng,Quan Liu
The infiltration and cytotoxicity of chimeric antigen receptor (CAR)-T cells are crucial for effective elimination of solid tumors. While metallo-immunotherapy is a promising strategy that can activate the antitumor immunity, its role in promoting CAR-T cell therapy remains elusive. The first single-element nanomaterial based on chromium nanoparticles (Cr NPs) for cancer photo-metallo-immunotherapy has been reported previously. Herein, an extended study using biodegradable polydopamine as a versatile carrier for these nanoparticles, enabling synergistic CAR-T cell therapy, is reported. The results show that these nanocomposites with or without further encapsulation of the anticancer drug alpelisib can promote the CAR-T cell migration and antitumor effect. Upon irradiation with near-infrared light, they caused mild hyperthermia that can “warm” the “cold” tumor microenvironment (TME). The administration of B7-H3 CAR-T cells to NOD severe combined immunodeficiency gamma mice bearing a human hepatoma or PIK3CA-mutated breast tumor can significantly inhibit the tumor growth after the induction of tumor hyperthermia by the nanocomposites and promote the secretion of serum cytokines, including IL-2, IFN-γ, and TNF-α. The trivalent Cr 3+ ions, which are the major degradation product of these nanocomposites, can increase the CXCL13 and CCL3 chemokine expressions to generate tertiary lymphoid structures (TLSs) in the tumor tissues, facilitating the CAR-T cell infiltration.
研究领域:
肿瘤学
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免疫疗法
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纳米技术
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生物医学工程
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癌症生物学
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产品关联
DOI
PubMed
高影响因子
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