The density and composition of lymphocytes infiltrating colon tumors serve as predictive factors for the clinical outcome of colon cancer.Our previous studies highlighted the potent anti-cancer properties of the princ...The density and composition of lymphocytes infiltrating colon tumors serve as predictive factors for the clinical outcome of colon cancer.Our previous studies highlighted the potent anti-cancer properties of the principal compounds found in Garcinia yunnanensis(YTE-17),attributing these effects to the regu-lation of multiple signaling pathways.However,knowledge regarding the mechanism and effect of YTE-17 in the prevention of colorectal cancer is limited.In this study,we conducted isobaric tags for relative and absolute quantification(iTRAQ)analysis on intestinal epithelial cells(IECs)exposed YTE-17,both in vitro and in vivo,revealing a significant inhibition of the Wnt family member 5a(Wnt5a)/c-Jun N-terminal kinase(JNK)signaling pathway.Subsequently,we elucidated the influence and mechanism of YTE-17 on the tumor microenvironment(TME),specifically focusing on macrophage-mediated T helper 17(Th17)cell induction in a colitis-associated cancer(CAC)model with Wnt5a deletion.Additionally,we performed the single-cell RNA sequencing(scRNA-seq)on the colonic tissue from the Wnt5a-deleted CAC model to characterize the composition,lineage,and functional status of immune mesenchymal cells during different stages of colorectal cancer(CRC)progression.Remarkably,our findings demon-strate a significant reduction in M2 macrophage polarization and Th17 cell phenotype upon treatment with YTE-17,leading to the restoration of regulatory T(Treg)/Th17 cell balance in azoxymethane(AOM)/dextran sodium sulfate(DSS)model.Furthermore,we also confirmed that YTE-17 effectively inhibited the glycolysis of Th17 cells in both direct and indirect co-culture systems with M2 macrophages.Notably,our study shed light on potential mechanisms linking the non-canonical Wnt5a/JNK signaling pathway and well-established canonical b-catenin oncogenic pathway in vivo.Specifically,we proposed that Wnt5a/JNK signaling activity in IECs promotes the development of cancer stem cells with b-catenin activity within the TME,involving macrophages and T cells.In summary,our study undergoes the po-tential of YTE-17 as a preventive strategy against CRC development by addressing the imbalance with the immune microenvironment,thereby mitigating the risk of malignancies.展开更多
Psoriasis is a common,chronic immune-mediated systemic disease that had no effective and durable treatment.Mesenchymal stem cells(MSCs)have immunomodulatory properties.Therefore,we performed a phase 1/2a,single-arm cl...Psoriasis is a common,chronic immune-mediated systemic disease that had no effective and durable treatment.Mesenchymal stem cells(MSCs)have immunomodulatory properties.Therefore,we performed a phase 1/2a,single-arm clinical trial to evaluate the safety and efficacy of human umbilical cord-derived MSCs(UMSCs)in the treatment of psoriasis and to preliminarily explore the possible mechanisms.Seventeen patients with psoriasis were enrolled and received UMsC infusions.Adverse events,laboratory parameters,PASl,and PGA were analyzed.We did not observe obvious side effects during the treatment and 6-month follow-up.A total of 47.1%(8/17)of the psoriasis patients had at least 40%improvement in the PASl score,and 17.6%(3/17)had no sign of disease or minimal disease based on the PGA score.And the efficiency was 25%(2/8)for males and 66.7%(6/9)for females.After UMSC transplantation(UMSCT),the frequencies of Tregs and CD4^(+)memory T cells were significantly increased,and the frequencies of T helper(Th)17 and CD4^(+)naive T cells were significantly decreased in peripheral blood(PB)of psoriasis patients.And all responders showed significant increases in Tregs and CD4^(+)memory T cells,and significant decreases in Th17 cells and serum IL-17 level after UMsCT.And baseline level of Tregs in responders were significantly lower than those in nonresponders.In conclusion,allogeneic UMSCT is safe and partially effective in psoriasis patients,and level of Tregs may be used as a potent biomarker to predict the clinical efficacy of UMSCT.Trial registration Clinical Trials NCT03765957.展开更多
Reproductive hormones associated with the hypothalamic-pituitary-gonadal(HPG)axis are closely linked to bone homeostasis.In this study,we demonstrate that Gonadotropin inhibitory hormone(GnIH,one of the key reproducti...Reproductive hormones associated with the hypothalamic-pituitary-gonadal(HPG)axis are closely linked to bone homeostasis.In this study,we demonstrate that Gonadotropin inhibitory hormone(GnIH,one of the key reproductive hormones upstream of the HPG axis)plays an indispensable role in regulating bone homeostasis and maintaining bone mass.We find that deficiency of GnIH or its receptor Gpr147 leads to a significant reduction in bone mineral density(BMD)in mice primarily by enhancement of osteoclast activation in vivo and in vitro.Mechanistically,GnIH/Gpr147 inhibits osteoclastogenesis by the PI3K/AKT,MAPK,NF-κB and Nfatc1 signaling pathways.Furthermore,GnIH treatment was able to alleviate bone loss in aging,ovariectomy(OVX)or LPS-induced mice.Moreover,the therapy using green light promotes the release of GnIH and rescues OVX-induced bone loss.In humans,serum GnIH increases and bone resorption markers decrease after green light exposure.Therefore,our study elucidates that GnIH plays an important role in maintaining bone homeostasis via modulating osteoclast differentiation and demonstrates the potential of GnIH therapy or green light therapy in preventing osteoporosis.展开更多
The mortality of patients with severe pneumonia caused by H1N1 infection is closely related to viral replication and cytokine storm.However,the specific mechanisms triggering virus replication and cytokine storm are s...The mortality of patients with severe pneumonia caused by H1N1 infection is closely related to viral replication and cytokine storm.However,the specific mechanisms triggering virus replication and cytokine storm are still not fully elucidated.Here,we identified hypoxia inducible factor-1α(HIF-1α)as one of the major host molecules that facilitates H1N1 virus replication followed by cytokine storm in alveolar epithelial cells.Specifically,HIF-1αprotein expression is upregulated after H1N1 infection.Deficiency of HIF-1αattenuates pulmonary injury,viral replication and cytokine storm in vivo.In addition,viral replication and cytokine storm were inhibited after HIF-1αknockdown in vitro.Mechanistically,the invasion of H1N1 virus into alveolar epithelial cells leads to a shift in glucose metabolism to glycolysis,with rapid production of ATP and lactate.Inhibition of glycolysis significantly suppresses viral replication and inflammatory responses.Further analysis revealed that H1N1-induced HIF-1αcan promote the expression of hexokinase 2(HK2),the key enzyme of glycolysis,and then not only provide energy for the rapid replication of H1N1 virus but also produce lactate,which reduces the accumulation of the MAVS/RIG-I complex and inhibits IFN-α/βproduction.In conclusion,this study demonstrated that the upregulation of HIF-1αby H1N1 infection augments viral replication and cytokine storm by cellular metabolic reprogramming toward glycolysis mainly through upregulation of HK2,providing a theoretical basis for finding potential targets for the treatment of severe pneumonia caused by H1N1 infection.展开更多
Elucidating the temporal process of immune remodeling under immunosuppressive treatment after liver transplantation(LT)is critical for precise clinical management strategies.Here,we performed a single-cell multi-omics...Elucidating the temporal process of immune remodeling under immunosuppressive treatment after liver transplantation(LT)is critical for precise clinical management strategies.Here,we performed a single-cell multi-omics analysis of peripheral blood mononuclear cells(PBMCs)collected from LT patients(with and without acute cellular rejection[ACR])at 13 time points.Validation was performed in two independent cohorts with additional LT patients and healthy controls.Our study revealed a four-phase recovery process after LT and delineated changes in immune cell composition,expression programs,and interactions along this process.The intensity of the immune response differs between the ACR and non-ACR patients.Notably,the newly identified inflamed NK cells,CD14+RNASE2+monocytes,and FOS-expressing monocytes emerged as predictive indicators of ACR.This study illuminates the longitudinal evolution of the immune cell landscape under tacrolimus-based immunosuppressive treatment during LT recovery,providing a four-phase framework that aids the clinical management of LT patients.展开更多
In a recent paper published in Nature,Lu et al.reveal a pivotal role of Nav1.8+nociceptor-released neuropeptide calcitonin generelated peptide(CGRP)in modulating the activities of myeloid cells during skin and muscle ...In a recent paper published in Nature,Lu et al.reveal a pivotal role of Nav1.8+nociceptor-released neuropeptide calcitonin generelated peptide(CGRP)in modulating the activities of myeloid cells during skin and muscle injury repair.This study demonstrated the significant impact of sensory neurons on injuryinduced inflammation and wound healing.展开更多
Sepsis is a heterogeneous syndrome induced by a dysregulated host response to infection.Glycolysis plays a role in maintaining the immune function of macrophages,which is crucial for severely septic patients.However,h...Sepsis is a heterogeneous syndrome induced by a dysregulated host response to infection.Glycolysis plays a role in maintaining the immune function of macrophages,which is crucial for severely septic patients.However,how the pathways that link glycolysis and macrophages are regulated is still largely unknown.Here,we provide evidence to support the function of KLF14,a novel Krüppel-like transcription factor,in the regulation of glycolysis and the immune function of macrophages during sepsis.KLF14 deletion led to significantly increased mortality in lethal models of murine endotoxemia and sepsis.Mechanistically,KLF14 decreased glycolysis and the secretion of inflammatory cytokines by macrophages by inhibiting the transcription of HK2.In addition,we confirmed that the expression of KLF14 was upregulated in septic patients.Furthermore,pharmacological activation of KLF14 conferred protection against sepsis in mice.These findings uncover a key role of KLF14 in modulating the inflammatory signaling pathway and shed light on the development of KLF14-targeted therapeutics for sepsis.展开更多
基金supported by“Jiaotong University Star”Program,China(Grant No.:YG2022QN082)the National Natural Science Foundation of China(Grant No.:82204887)+1 种基金the Science Foundation for Shanghai Committee of Science Project,China(Grant Nos.:21S21901400,23S21901200)the Natural Science Research Foundation of Jiading District,China(Grant No.:JDKW-2021-0023).
文摘The density and composition of lymphocytes infiltrating colon tumors serve as predictive factors for the clinical outcome of colon cancer.Our previous studies highlighted the potent anti-cancer properties of the principal compounds found in Garcinia yunnanensis(YTE-17),attributing these effects to the regu-lation of multiple signaling pathways.However,knowledge regarding the mechanism and effect of YTE-17 in the prevention of colorectal cancer is limited.In this study,we conducted isobaric tags for relative and absolute quantification(iTRAQ)analysis on intestinal epithelial cells(IECs)exposed YTE-17,both in vitro and in vivo,revealing a significant inhibition of the Wnt family member 5a(Wnt5a)/c-Jun N-terminal kinase(JNK)signaling pathway.Subsequently,we elucidated the influence and mechanism of YTE-17 on the tumor microenvironment(TME),specifically focusing on macrophage-mediated T helper 17(Th17)cell induction in a colitis-associated cancer(CAC)model with Wnt5a deletion.Additionally,we performed the single-cell RNA sequencing(scRNA-seq)on the colonic tissue from the Wnt5a-deleted CAC model to characterize the composition,lineage,and functional status of immune mesenchymal cells during different stages of colorectal cancer(CRC)progression.Remarkably,our findings demon-strate a significant reduction in M2 macrophage polarization and Th17 cell phenotype upon treatment with YTE-17,leading to the restoration of regulatory T(Treg)/Th17 cell balance in azoxymethane(AOM)/dextran sodium sulfate(DSS)model.Furthermore,we also confirmed that YTE-17 effectively inhibited the glycolysis of Th17 cells in both direct and indirect co-culture systems with M2 macrophages.Notably,our study shed light on potential mechanisms linking the non-canonical Wnt5a/JNK signaling pathway and well-established canonical b-catenin oncogenic pathway in vivo.Specifically,we proposed that Wnt5a/JNK signaling activity in IECs promotes the development of cancer stem cells with b-catenin activity within the TME,involving macrophages and T cells.In summary,our study undergoes the po-tential of YTE-17 as a preventive strategy against CRC development by addressing the imbalance with the immune microenvironment,thereby mitigating the risk of malignancies.
基金This study was sponsored by The National Key Research and Development Project of China(2020YFA0112900,2018YFC0117004)The National Natural Science Foundation of China(82073447,81573049)+1 种基金The Key Research and Development Program of Hunan Province(2018SK2082)The Research and Development Project of Hunan Guangxiu High-tech Life Technology Co,Ltd(2019RES08).
文摘Psoriasis is a common,chronic immune-mediated systemic disease that had no effective and durable treatment.Mesenchymal stem cells(MSCs)have immunomodulatory properties.Therefore,we performed a phase 1/2a,single-arm clinical trial to evaluate the safety and efficacy of human umbilical cord-derived MSCs(UMSCs)in the treatment of psoriasis and to preliminarily explore the possible mechanisms.Seventeen patients with psoriasis were enrolled and received UMsC infusions.Adverse events,laboratory parameters,PASl,and PGA were analyzed.We did not observe obvious side effects during the treatment and 6-month follow-up.A total of 47.1%(8/17)of the psoriasis patients had at least 40%improvement in the PASl score,and 17.6%(3/17)had no sign of disease or minimal disease based on the PGA score.And the efficiency was 25%(2/8)for males and 66.7%(6/9)for females.After UMSC transplantation(UMSCT),the frequencies of Tregs and CD4^(+)memory T cells were significantly increased,and the frequencies of T helper(Th)17 and CD4^(+)naive T cells were significantly decreased in peripheral blood(PB)of psoriasis patients.And all responders showed significant increases in Tregs and CD4^(+)memory T cells,and significant decreases in Th17 cells and serum IL-17 level after UMsCT.And baseline level of Tregs in responders were significantly lower than those in nonresponders.In conclusion,allogeneic UMSCT is safe and partially effective in psoriasis patients,and level of Tregs may be used as a potent biomarker to predict the clinical efficacy of UMSCT.Trial registration Clinical Trials NCT03765957.
基金National Key Research and Development Program of China(2023YFB3810200 to J.L.)National Natural Science Foundation of China(92168204,82225030 to J.L.)Fundamental Research Funds for the Central Universities(22120210586 to J.L.)。
文摘Reproductive hormones associated with the hypothalamic-pituitary-gonadal(HPG)axis are closely linked to bone homeostasis.In this study,we demonstrate that Gonadotropin inhibitory hormone(GnIH,one of the key reproductive hormones upstream of the HPG axis)plays an indispensable role in regulating bone homeostasis and maintaining bone mass.We find that deficiency of GnIH or its receptor Gpr147 leads to a significant reduction in bone mineral density(BMD)in mice primarily by enhancement of osteoclast activation in vivo and in vitro.Mechanistically,GnIH/Gpr147 inhibits osteoclastogenesis by the PI3K/AKT,MAPK,NF-κB and Nfatc1 signaling pathways.Furthermore,GnIH treatment was able to alleviate bone loss in aging,ovariectomy(OVX)or LPS-induced mice.Moreover,the therapy using green light promotes the release of GnIH and rescues OVX-induced bone loss.In humans,serum GnIH increases and bone resorption markers decrease after green light exposure.Therefore,our study elucidates that GnIH plays an important role in maintaining bone homeostasis via modulating osteoclast differentiation and demonstrates the potential of GnIH therapy or green light therapy in preventing osteoporosis.
基金supported by a grant from the National Natural Science Foundation of China(No.82072210)the Shanghai Municipal Science and Technology Commission,China(No.20ZR1445200)+1 种基金the Chinese Federation of Public Health Foundation(GWLM202001)the Three-Year Initiative Plan for Strengthening Public Health System Construction in Shanghai(No.GWV-10.1-XK25).
文摘The mortality of patients with severe pneumonia caused by H1N1 infection is closely related to viral replication and cytokine storm.However,the specific mechanisms triggering virus replication and cytokine storm are still not fully elucidated.Here,we identified hypoxia inducible factor-1α(HIF-1α)as one of the major host molecules that facilitates H1N1 virus replication followed by cytokine storm in alveolar epithelial cells.Specifically,HIF-1αprotein expression is upregulated after H1N1 infection.Deficiency of HIF-1αattenuates pulmonary injury,viral replication and cytokine storm in vivo.In addition,viral replication and cytokine storm were inhibited after HIF-1αknockdown in vitro.Mechanistically,the invasion of H1N1 virus into alveolar epithelial cells leads to a shift in glucose metabolism to glycolysis,with rapid production of ATP and lactate.Inhibition of glycolysis significantly suppresses viral replication and inflammatory responses.Further analysis revealed that H1N1-induced HIF-1αcan promote the expression of hexokinase 2(HK2),the key enzyme of glycolysis,and then not only provide energy for the rapid replication of H1N1 virus but also produce lactate,which reduces the accumulation of the MAVS/RIG-I complex and inhibits IFN-α/βproduction.In conclusion,this study demonstrated that the upregulation of HIF-1αby H1N1 infection augments viral replication and cytokine storm by cellular metabolic reprogramming toward glycolysis mainly through upregulation of HK2,providing a theoretical basis for finding potential targets for the treatment of severe pneumonia caused by H1N1 infection.
基金This work received financial support from the National Natural Science Foundation of China(no.82070677 and 82201964)Natural Science and Technology Major Project of the Xiamen(no.3502Z20231034)+1 种基金Natural Science Fund for Distinguished Young Scholars of Fujian Province(no.2023J01310519)Natural Science Foundation of Xiamen(no.3502Z20227283 and 3502Z20227122).
文摘Elucidating the temporal process of immune remodeling under immunosuppressive treatment after liver transplantation(LT)is critical for precise clinical management strategies.Here,we performed a single-cell multi-omics analysis of peripheral blood mononuclear cells(PBMCs)collected from LT patients(with and without acute cellular rejection[ACR])at 13 time points.Validation was performed in two independent cohorts with additional LT patients and healthy controls.Our study revealed a four-phase recovery process after LT and delineated changes in immune cell composition,expression programs,and interactions along this process.The intensity of the immune response differs between the ACR and non-ACR patients.Notably,the newly identified inflamed NK cells,CD14+RNASE2+monocytes,and FOS-expressing monocytes emerged as predictive indicators of ACR.This study illuminates the longitudinal evolution of the immune cell landscape under tacrolimus-based immunosuppressive treatment during LT recovery,providing a four-phase framework that aids the clinical management of LT patients.
基金This commentary was supported by funds from the European Research Council Consolidator Grant(ERC-CoG 819933)the LEO Foundation(LF-OC-21-000835)+2 种基金the European Foundation for the Study of Diabetes Anniversary Fund Programme 2021(EFSD#98201)the Marie Curie Innovative Training Network(955722 SkinTERM)the German Research Foundation(CRC-359 PILOT).
文摘In a recent paper published in Nature,Lu et al.reveal a pivotal role of Nav1.8+nociceptor-released neuropeptide calcitonin generelated peptide(CGRP)in modulating the activities of myeloid cells during skin and muscle injury repair.This study demonstrated the significant impact of sensory neurons on injuryinduced inflammation and wound healing.
基金This work was supported by the National Natural Science Foundation of China(81701943,81971813).
文摘Sepsis is a heterogeneous syndrome induced by a dysregulated host response to infection.Glycolysis plays a role in maintaining the immune function of macrophages,which is crucial for severely septic patients.However,how the pathways that link glycolysis and macrophages are regulated is still largely unknown.Here,we provide evidence to support the function of KLF14,a novel Krüppel-like transcription factor,in the regulation of glycolysis and the immune function of macrophages during sepsis.KLF14 deletion led to significantly increased mortality in lethal models of murine endotoxemia and sepsis.Mechanistically,KLF14 decreased glycolysis and the secretion of inflammatory cytokines by macrophages by inhibiting the transcription of HK2.In addition,we confirmed that the expression of KLF14 was upregulated in septic patients.Furthermore,pharmacological activation of KLF14 conferred protection against sepsis in mice.These findings uncover a key role of KLF14 in modulating the inflammatory signaling pathway and shed light on the development of KLF14-targeted therapeutics for sepsis.
