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:Macrophages are a major component of the tumor microenvironment.M1 macrophages secrete pro-inflammatory factors that inhibit tumor growth and development,whereas tumor-associated macrophages(TAMs)mainly exhi...Objective:Macrophages are a major component of the tumor microenvironment.M1 macrophages secrete pro-inflammatory factors that inhibit tumor growth and development,whereas tumor-associated macrophages(TAMs)mainly exhibit an M2 phenotype.Our previous studies have shown that the interleukin-33/ST2(IL-33/ST2)axis is essential for activation of the M1 phenotype.This study investigates the role of the IL-33/ST2 axis in TAMs,its effects on tumor growth,and whether it participates in the mutual conversion between the M1 and M2 phenotypes.Methods:Bone marrow-derived macrophages were extracted from wildtype,ST2 knockout(ST2-/-),and Il33-overexpressing mice and differentiated with IL-4.The mitochondrial and lysosomal number and location,and the expression of related proteins were used to analyze mitophagy.Oxygen consumption rates and glucose and lactate levels were measured to reveal metabolic changes.Results:The IL-33/ST2 axis was demonstrated to play an important role in the metabolic conversion of macrophages from OXPHOS to glycolysis by altering mitophagy levels.The IL-33/ST2 axis promoted enhanced cell oxidative phosphorylation,thereby further increasing M2 polarization gene expression and ultimately promoting tumor growth(P<0.05)(Figure 4).This metabolic shift was not due to mitochondrial damage,because the mitochondrial membrane potential was not significantly altered by IL-4 stimulation or ST2 knockout;however,it might be associated with the m TOR activity.Conclusions:These results clarify the interaction between the IL-33/ST2 pathway and macrophage polarization,and may pave the way to the development of new cancer immunotherapies targeting the IL-33/ST2 axis.展开更多
The IL-33/ST2 axis has been implicated in the pathogenesis of several tissue-specific autoimmune diseases. Celiac disease （CD） is the only autoimmune disease in which both the major genetic factors （HLA-DQ2/DQ8） a...The IL-33/ST2 axis has been implicated in the pathogenesis of several tissue-specific autoimmune diseases. Celiac disease （CD） is the only autoimmune disease in which both the major genetic factors （HLA-DQ2/DQ8） and etiologic ones （dietary gluten） for susceptibility are known. We have measured serum levels and determined intestinal tissue expression of IL-33 and its receptor soluble ST2 in patients with CD to investigate their association with disease activity. Serum and tissue levels of both IL-33 and sST2 were significantly higher in patients with CD compared with those in control patients without CD. We show that toxic peptides extracted from barley and wheat gliadin significantly stimulate the production of IL-33 and ST2 in cultured peripheral blood mononuclear cell from celiac patients, strongly implicating the IL-33/ST2 axis in the pathogenesis of CD. The higher levels of IL-33 and its receptor ST2 in tissue and serum reflect an active inflammatory state and may represent a potential biomarker for disease activity. A better understanding of IL-33/ ST2 release, mode of action, and regulation will be crucial to develop therapeutics that target the IL-33/ST2 pathway to treat CD.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
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 grants from the National Natural Science Foundation of China(Grant Nos.81672948 and 81772794)Jilin Provincial Research Foundation for Health Technology Innovation(Grant No.2019J009)+1 种基金Jilin Provincial Research Foundation for the Development of Science and Technology Projects(Grant Nos.20191004004TC and 20190103095JH)Jilin Provincial Industrial Innovation Project(Grant No.2018C052-7)。
文摘Objective:Macrophages are a major component of the tumor microenvironment.M1 macrophages secrete pro-inflammatory factors that inhibit tumor growth and development,whereas tumor-associated macrophages(TAMs)mainly exhibit an M2 phenotype.Our previous studies have shown that the interleukin-33/ST2(IL-33/ST2)axis is essential for activation of the M1 phenotype.This study investigates the role of the IL-33/ST2 axis in TAMs,its effects on tumor growth,and whether it participates in the mutual conversion between the M1 and M2 phenotypes.Methods:Bone marrow-derived macrophages were extracted from wildtype,ST2 knockout(ST2-/-),and Il33-overexpressing mice and differentiated with IL-4.The mitochondrial and lysosomal number and location,and the expression of related proteins were used to analyze mitophagy.Oxygen consumption rates and glucose and lactate levels were measured to reveal metabolic changes.Results:The IL-33/ST2 axis was demonstrated to play an important role in the metabolic conversion of macrophages from OXPHOS to glycolysis by altering mitophagy levels.The IL-33/ST2 axis promoted enhanced cell oxidative phosphorylation,thereby further increasing M2 polarization gene expression and ultimately promoting tumor growth(P<0.05)(Figure 4).This metabolic shift was not due to mitochondrial damage,because the mitochondrial membrane potential was not significantly altered by IL-4 stimulation or ST2 knockout;however,it might be associated with the m TOR activity.Conclusions:These results clarify the interaction between the IL-33/ST2 pathway and macrophage polarization,and may pave the way to the development of new cancer immunotherapies targeting the IL-33/ST2 axis.
文摘The IL-33/ST2 axis has been implicated in the pathogenesis of several tissue-specific autoimmune diseases. Celiac disease （CD） is the only autoimmune disease in which both the major genetic factors （HLA-DQ2/DQ8） and etiologic ones （dietary gluten） for susceptibility are known. We have measured serum levels and determined intestinal tissue expression of IL-33 and its receptor soluble ST2 in patients with CD to investigate their association with disease activity. Serum and tissue levels of both IL-33 and sST2 were significantly higher in patients with CD compared with those in control patients without CD. We show that toxic peptides extracted from barley and wheat gliadin significantly stimulate the production of IL-33 and ST2 in cultured peripheral blood mononuclear cell from celiac patients, strongly implicating the IL-33/ST2 axis in the pathogenesis of CD. The higher levels of IL-33 and its receptor ST2 in tissue and serum reflect an active inflammatory state and may represent a potential biomarker for disease activity. A better understanding of IL-33/ ST2 release, mode of action, and regulation will be crucial to develop therapeutics that target the IL-33/ST2 pathway to treat CD.
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.
