Background:Repetitive mild traumatic brain injury(rmTBI)is a significant risk factor for neurodegeneration,characterized by pathological protein deposition and persistent neuroinflammation.Research has observed increa...Background:Repetitive mild traumatic brain injury(rmTBI)is a significant risk factor for neurodegeneration,characterized by pathological protein deposition and persistent neuroinflammation.Research has observed increased interleukin-33(IL-33)levels in the peripheral blood of patients with rmTBI,suggesting IL-33 may participate in regulating the pathological development of rmTBI.The study aims to elucidate the impact and mechanism of IL-33 in the progression of neuropathology following rmTBI,and to explore its potential as a therapeutic target to improve the neurological outcome.Methods:The study employed an rmTBI mouse model using the wild-type(WT)and IL-33 knockout mice.Cognitive function was assessed via the Y-maze and Barnes tests.The main cell type expressing IL-33 and its receptor,suppression of tumorigenicity 2(ST2),was then investigated in the mouse brain through immunofluorescence colocalization.As the primary neural cell responsible for ST2 expression,microglia were studied in vitro using the BV2 cell line.The effects of lipid droplets(LDs)accumulation and amyloid-beta(Aβ)phagocytosis were measured to elucidate the impact of IL-33 on BV2 cells'phagocytosis.Additionally,HT22 neuronal apoptosis was assessed by flow cytometry.Finally,the cognitive effects of intranasal administration of IL-33 were evaluated in mice.Results:IL-33 KO mice exhibited pronounced cognitive impairment after rmTBI.In the mouse brain,astrocytes were identified as the primary source of IL-33 secretion,while microglia predominantly expressed ST2.Transcriptome sequencing revealed that IL-33 significantly influenced phagocytosis function.IL-33 mitigated LDs accumulation in BV2 cells and enhanced Aβphagocytosis in vitro.In addition,the culture medium of BV2 cells with activated IL-33/ST2 signaling reduced HT22 neuronal apoptosis and axonal damage.Furthermore,intranasal administration of IL-33 was observed to be effective in alleviating neurodegeneration and cognitive outcome of rmTBI mice.Conclusions:Dysfunction of the IL-33/ST2 axis following rmTBI leads to cognitive dysfunction via impairing microglial phagocytosis capacity and promoting neuronal damage.IL-33 would be a promising therapeutic target for alleviating neurodegeneration following rmTBI.展开更多
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
白细胞介素-33 (IL-33)是一种与多种免疫调节过程相关的细胞因子,它在免疫调节、炎症反应以及多种疾病的发生发展过程中发挥着重要作用,亦在维持妊娠状态下的免疫稳态中扮演重要角色。母胎界面由滋养细胞、蜕膜基质细胞及蜕膜免疫细胞构...白细胞介素-33 (IL-33)是一种与多种免疫调节过程相关的细胞因子,它在免疫调节、炎症反应以及多种疾病的发生发展过程中发挥着重要作用,亦在维持妊娠状态下的免疫稳态中扮演重要角色。母胎界面由滋养细胞、蜕膜基质细胞及蜕膜免疫细胞构成,其中蜕膜免疫细胞包括自然杀伤(NK)细胞、T细胞、B细胞、巨噬细胞、树突状细胞等。妊娠过程中,胎儿对于母体而言为同种半异体移植物,因此保持母胎界面的免疫平衡尤为重要,而本文通过研究IL-33对于蜕膜免疫细胞的影响及相关机制的研究进展,从而进一步探索了妊娠过程中母胎局部免疫平衡的维持。Interleukin-33 (IL-33) is a cytokine involved in a variety of immunomodulatory processes, which plays an important role in immune regulation, inflammation and the occurrence and development of various diseases, and also plays an important role in the maintenance of immune homeostasis during pregnancy. The maternal-fetal interface is composed of trophoblast cells, decidual stromal cells and decidual immune cells, among which decidual immune cells include natural killer (NK) cells, T cells, B cells, macrophages and dendritic cells. During pregnancy, the fetus is an allogeneic and semi-allogeneic graft from the mother, so it is particularly important to maintain the immune balance at the mother-fetus interface. In this paper, the influence of IL-33 on decidual immune cells and the related mechanisms have been studied, so as to further explore the maintenance of the local immune balance in the mother and fetus during pregnancy.展开更多
基金supported by the National Natural Science Foundation of China(82271401,82071394)the Tianjin Health Research Project(TJWJ2024RC002)。
文摘Background:Repetitive mild traumatic brain injury(rmTBI)is a significant risk factor for neurodegeneration,characterized by pathological protein deposition and persistent neuroinflammation.Research has observed increased interleukin-33(IL-33)levels in the peripheral blood of patients with rmTBI,suggesting IL-33 may participate in regulating the pathological development of rmTBI.The study aims to elucidate the impact and mechanism of IL-33 in the progression of neuropathology following rmTBI,and to explore its potential as a therapeutic target to improve the neurological outcome.Methods:The study employed an rmTBI mouse model using the wild-type(WT)and IL-33 knockout mice.Cognitive function was assessed via the Y-maze and Barnes tests.The main cell type expressing IL-33 and its receptor,suppression of tumorigenicity 2(ST2),was then investigated in the mouse brain through immunofluorescence colocalization.As the primary neural cell responsible for ST2 expression,microglia were studied in vitro using the BV2 cell line.The effects of lipid droplets(LDs)accumulation and amyloid-beta(Aβ)phagocytosis were measured to elucidate the impact of IL-33 on BV2 cells'phagocytosis.Additionally,HT22 neuronal apoptosis was assessed by flow cytometry.Finally,the cognitive effects of intranasal administration of IL-33 were evaluated in mice.Results:IL-33 KO mice exhibited pronounced cognitive impairment after rmTBI.In the mouse brain,astrocytes were identified as the primary source of IL-33 secretion,while microglia predominantly expressed ST2.Transcriptome sequencing revealed that IL-33 significantly influenced phagocytosis function.IL-33 mitigated LDs accumulation in BV2 cells and enhanced Aβphagocytosis in vitro.In addition,the culture medium of BV2 cells with activated IL-33/ST2 signaling reduced HT22 neuronal apoptosis and axonal damage.Furthermore,intranasal administration of IL-33 was observed to be effective in alleviating neurodegeneration and cognitive outcome of rmTBI mice.Conclusions:Dysfunction of the IL-33/ST2 axis following rmTBI leads to cognitive dysfunction via impairing microglial phagocytosis capacity and promoting neuronal damage.IL-33 would be a promising therapeutic target for alleviating neurodegeneration following rmTBI.
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.
文摘白细胞介素-33 (IL-33)是一种与多种免疫调节过程相关的细胞因子,它在免疫调节、炎症反应以及多种疾病的发生发展过程中发挥着重要作用,亦在维持妊娠状态下的免疫稳态中扮演重要角色。母胎界面由滋养细胞、蜕膜基质细胞及蜕膜免疫细胞构成,其中蜕膜免疫细胞包括自然杀伤(NK)细胞、T细胞、B细胞、巨噬细胞、树突状细胞等。妊娠过程中,胎儿对于母体而言为同种半异体移植物,因此保持母胎界面的免疫平衡尤为重要,而本文通过研究IL-33对于蜕膜免疫细胞的影响及相关机制的研究进展,从而进一步探索了妊娠过程中母胎局部免疫平衡的维持。Interleukin-33 (IL-33) is a cytokine involved in a variety of immunomodulatory processes, which plays an important role in immune regulation, inflammation and the occurrence and development of various diseases, and also plays an important role in the maintenance of immune homeostasis during pregnancy. The maternal-fetal interface is composed of trophoblast cells, decidual stromal cells and decidual immune cells, among which decidual immune cells include natural killer (NK) cells, T cells, B cells, macrophages and dendritic cells. During pregnancy, the fetus is an allogeneic and semi-allogeneic graft from the mother, so it is particularly important to maintain the immune balance at the mother-fetus interface. In this paper, the influence of IL-33 on decidual immune cells and the related mechanisms have been studied, so as to further explore the maintenance of the local immune balance in the mother and fetus during pregnancy.
