IL-33 and its receptor ST2 play crucial roles in tissue repair and homeostasis.However,their involvement in optic neuropathy due to trauma and glaucoma remains unclear.Here,we report that IL-33 and ST2 were highly exp...IL-33 and its receptor ST2 play crucial roles in tissue repair and homeostasis.However,their involvement in optic neuropathy due to trauma and glaucoma remains unclear.Here,we report that IL-33 and ST2 were highly expressed in the mouse optic nerve and retina.Deletion of IL-33 or ST2 exacerbated retinal ganglion cell(RGC)loss,retinal thinning,and nerve fiber degeneration following optic nerve(ON)injury.This heightened retinal neurodegeneration correlated with increased neurotoxic astrocytes in Il33-/-mice.In vitro,rIL-33 mitigated the neurotoxic astrocyte phenotype and reduced the expression of pro-inflammatory factors,thereby alleviating the RGC death induced by neurotoxic astrocyte-conditioned medium in retinal explants.Exogenous IL-33 treatment improved RGC survival in Il33-/-and WT mice after ON injury,but not in ST2-/-mice.Our findings highlight the role of the IL-33/ST2 axis in modulating reactive astrocyte function and providing neuroprotection for RGCs following ON injury.展开更多
Objective:Suppression of tumorigenicity 2(ST2),the receptor for interleukin(IL)-33,has a critical role in tumor growth,angiogenesis,metastasis,and immune modulation.The IL-33/ST2 pathway is known to influence the pola...Objective:Suppression of tumorigenicity 2(ST2),the receptor for interleukin(IL)-33,has a critical role in tumor growth,angiogenesis,metastasis,and immune modulation.The IL-33/ST2 pathway is known to influence the polarization and function of macrophages,which is integral to modulating the tumor microenvironment.However,the precise role of IL-33/ST2 in tumors,particularly non-small cell lung cancer(NSCLC),has not been established.Methods:ST2 expression in NSCLC was analysed using a murine model and patient specimens.The effect of the IL-33/ST2 axis on macrophage polarization in NSCLC was determined.Results:Elevated ST2 expression was correlated with aggressive tumor growth.Specifically,ST2 expression on macrophages was associated with lung cancer progression and the absence of ST2 on macrophages was associated with diminished tumor growth.IL-33 promoted polarization of alternatively activated macrophages in an ST2-dependent manner that was mediated via the PI3K/Akt signalling pathway.Moreover,IL-33 inhibited T-cell function by inducing the secretion of transforming growth factorβfrom alternatively activated macrophages.Conclusions:Macrophages expressing ST2 can serve as promising therapeutic targets for NSCLC immunotherapy,highlighting the IL-33/ST2 axis as a potential target for future antitumor strategies.展开更多
目的观察rhIL-33对人胚肺成纤维细胞增殖及其间充质细胞标记物的影响,探讨IL-33/ST2L-TRAF信号通路在肺纤维化形成过程中的作用。方法培养HELF细胞,PCR检测IL-33受体ST2L m RNA;不同浓度梯度的rh IL-33刺激细胞,MTT法检测不同时间点（24...目的观察rhIL-33对人胚肺成纤维细胞增殖及其间充质细胞标记物的影响,探讨IL-33/ST2L-TRAF信号通路在肺纤维化形成过程中的作用。方法培养HELF细胞,PCR检测IL-33受体ST2L m RNA;不同浓度梯度的rh IL-33刺激细胞,MTT法检测不同时间点（24、48、72 h）IL-33对HF细胞增殖的影响;Real-time PCR方法检测IL-33刺激HELF后不同时间点（0、6、12、24、48、72 h）细胞标志性基因α-SMA m RNA、Vimentin m RNA、collagn I m RNA及TRAF-6 m RNA的变化;Western blot法检测细胞标志性蛋白α-平滑肌肌动蛋白（α-SMA）、波形蛋白（Vimentin）、I型胶原（collagen I）及关键性信号分子TRAF-6与下游信号分子ERK1/2、JNK、NF-kappa B等的改变。结果 IL-33能促进HELF的增殖,10 ng/ml的IL-33促增殖作用最强,且72 h最为明显;随着IL-33刺激细胞时间的逐渐延长,在0～72 h内α-SMA、Vimentin、collagen I在基因与蛋白水平均先上调后下调,信号分子TRAF-6、ERK1/2、JNK、NF-kappa B（P65）等亦呈现先上调后下调的趋势。结论 IL-33能促进HELF细胞增殖、活化及合成胶原,IL-33/ST2L-TRAF-6通路在此过程中起了关键作用,尤其是在病变早期炎症过程中作用最为明显。展开更多
基金supported by the National Natural Science Foundation of China(31670876 and 82171761).
文摘IL-33 and its receptor ST2 play crucial roles in tissue repair and homeostasis.However,their involvement in optic neuropathy due to trauma and glaucoma remains unclear.Here,we report that IL-33 and ST2 were highly expressed in the mouse optic nerve and retina.Deletion of IL-33 or ST2 exacerbated retinal ganglion cell(RGC)loss,retinal thinning,and nerve fiber degeneration following optic nerve(ON)injury.This heightened retinal neurodegeneration correlated with increased neurotoxic astrocytes in Il33-/-mice.In vitro,rIL-33 mitigated the neurotoxic astrocyte phenotype and reduced the expression of pro-inflammatory factors,thereby alleviating the RGC death induced by neurotoxic astrocyte-conditioned medium in retinal explants.Exogenous IL-33 treatment improved RGC survival in Il33-/-and WT mice after ON injury,but not in ST2-/-mice.Our findings highlight the role of the IL-33/ST2 axis in modulating reactive astrocyte function and providing neuroprotection for RGCs following ON injury.
基金supported by the National Key R&D Program of China(2023YFC2413100)the National Natural Science Foundation of China(No.81501423)the Fundamental Research Funds for the Central Universities。
文摘Objective:Suppression of tumorigenicity 2(ST2),the receptor for interleukin(IL)-33,has a critical role in tumor growth,angiogenesis,metastasis,and immune modulation.The IL-33/ST2 pathway is known to influence the polarization and function of macrophages,which is integral to modulating the tumor microenvironment.However,the precise role of IL-33/ST2 in tumors,particularly non-small cell lung cancer(NSCLC),has not been established.Methods:ST2 expression in NSCLC was analysed using a murine model and patient specimens.The effect of the IL-33/ST2 axis on macrophage polarization in NSCLC was determined.Results:Elevated ST2 expression was correlated with aggressive tumor growth.Specifically,ST2 expression on macrophages was associated with lung cancer progression and the absence of ST2 on macrophages was associated with diminished tumor growth.IL-33 promoted polarization of alternatively activated macrophages in an ST2-dependent manner that was mediated via the PI3K/Akt signalling pathway.Moreover,IL-33 inhibited T-cell function by inducing the secretion of transforming growth factorβfrom alternatively activated macrophages.Conclusions:Macrophages expressing ST2 can serve as promising therapeutic targets for NSCLC immunotherapy,highlighting the IL-33/ST2 axis as a potential target for future antitumor strategies.
文摘目的观察rhIL-33对人胚肺成纤维细胞增殖及其间充质细胞标记物的影响,探讨IL-33/ST2L-TRAF信号通路在肺纤维化形成过程中的作用。方法培养HELF细胞,PCR检测IL-33受体ST2L m RNA;不同浓度梯度的rh IL-33刺激细胞,MTT法检测不同时间点（24、48、72 h）IL-33对HF细胞增殖的影响;Real-time PCR方法检测IL-33刺激HELF后不同时间点（0、6、12、24、48、72 h）细胞标志性基因α-SMA m RNA、Vimentin m RNA、collagn I m RNA及TRAF-6 m RNA的变化;Western blot法检测细胞标志性蛋白α-平滑肌肌动蛋白（α-SMA）、波形蛋白（Vimentin）、I型胶原（collagen I）及关键性信号分子TRAF-6与下游信号分子ERK1/2、JNK、NF-kappa B等的改变。结果 IL-33能促进HELF的增殖,10 ng/ml的IL-33促增殖作用最强,且72 h最为明显;随着IL-33刺激细胞时间的逐渐延长,在0～72 h内α-SMA、Vimentin、collagen I在基因与蛋白水平均先上调后下调,信号分子TRAF-6、ERK1/2、JNK、NF-kappa B（P65）等亦呈现先上调后下调的趋势。结论 IL-33能促进HELF细胞增殖、活化及合成胶原,IL-33/ST2L-TRAF-6通路在此过程中起了关键作用,尤其是在病变早期炎症过程中作用最为明显。
