Aging is a significant risk factor for various diseases,including asthma,and it often leads to poorer clinical outcomes,particularly in elderly individuals.It is recognized that age-related diseases are due to a time-...Aging is a significant risk factor for various diseases,including asthma,and it often leads to poorer clinical outcomes,particularly in elderly individuals.It is recognized that age-related diseases are due to a time-dependent accumulation of cellular damage,resulting in a progressive decline in cellular and physiological functions and an increased susceptibility to chronic diseases.The effects of aging affect not only the elderly but also those of younger ages,posing significant challenges to global healthcare.Thus,understanding the molecular mechanisms associated with aging in different diseases is essential.One intriguing factor is the aryl hydrocarbon receptor(AhR),which serves as a cytoplasmic receptor and ligand-activated transcription factor and has been linked to the aging process.Here,we review the literature on several major hallmarks of aging,including mitochondrial dysfunction,cellular senescence,autophagy,mitophagy,epigenetic alterations,and microbiome disturbances.Moreover,we provide an overview of the impact of AhR on these hallmarks by mediating responses to environmental exposures,particularly in relation to the immune system.Furthermore,we explore how aging hallmarks affect clinical characteristics,inflammatory features,exacerbations,and the treatment of asthma.It is suggested that AhR signaling may potentially play a role in regulating asthma phenotypes in elderly populations as part of the aging process.展开更多
Cytokine storms are crucial in the development of various inflammatory diseases,including sepsis and autoimmune disorders.The immunosuppressive cytokine INTERLEUKIN(IL)-37 consists of five isoforms(IL-37a-e).We identi...Cytokine storms are crucial in the development of various inflammatory diseases,including sepsis and autoimmune disorders.The immunosuppressive cytokine INTERLEUKIN(IL)-37 consists of five isoforms(IL-37a-e).We identified IL-37a as a nuclear cytokine for the first time.Compared to IL-37b,IL-37a demonstrated greater efficacy in protecting against Toll-like receptor-induced cytokine hypersecretion and lethal endotoxic shock.The full-length(FL)form of IL-37a and the N-terminal fragment,which is processed by elastase,could translocate into cell nuclei through a distinctive nuclear localization sequence(NLS)/importin nuclear transport pathway.These forms exerted their regulatory effects independent of the IL-1R8 receptor by transcriptionally upregulating the nuclear receptor peroxisome proliferator-activated receptor(PPARγ).This process involved the recruitment of the H3K4 methyltransferase complex WDR5/MLL4/C/EBPβand H3K4me1/2 to the enhancer/promoter of Pparg.The receptor-independent regulatory pathway of the nuclear IL-37a–PPARγaxis and receptor-dependent signaling by secreted IL-37a maintain homeostasis and are potential therapeutic targets for various inflammatory diseases,including sepsis.展开更多
基金supported by grants from the US National Institutes of Health(NIH)(Nos.1R01AI153331 and R01AI141642)the Department of Science and Technology of Yunnan Province,China(No.202201AY070001-260)
文摘Aging is a significant risk factor for various diseases,including asthma,and it often leads to poorer clinical outcomes,particularly in elderly individuals.It is recognized that age-related diseases are due to a time-dependent accumulation of cellular damage,resulting in a progressive decline in cellular and physiological functions and an increased susceptibility to chronic diseases.The effects of aging affect not only the elderly but also those of younger ages,posing significant challenges to global healthcare.Thus,understanding the molecular mechanisms associated with aging in different diseases is essential.One intriguing factor is the aryl hydrocarbon receptor(AhR),which serves as a cytoplasmic receptor and ligand-activated transcription factor and has been linked to the aging process.Here,we review the literature on several major hallmarks of aging,including mitochondrial dysfunction,cellular senescence,autophagy,mitophagy,epigenetic alterations,and microbiome disturbances.Moreover,we provide an overview of the impact of AhR on these hallmarks by mediating responses to environmental exposures,particularly in relation to the immune system.Furthermore,we explore how aging hallmarks affect clinical characteristics,inflammatory features,exacerbations,and the treatment of asthma.It is suggested that AhR signaling may potentially play a role in regulating asthma phenotypes in elderly populations as part of the aging process.
基金support from Versus Arthritis UK(21327 to D.X.)the National Key R&D Program of China(2021YFC2701800 and 2021YFC2701802 to Y.Z.),the National Natural Science Foundation of China(82241038,81974248 to Y.Z.and 81900751 to X.H.)+5 种基金the International Joint Laboratory Program of National Children’s Medical Center(EK1125180109 to Y.Z.)the Program for Outstanding Medical Academic Leader(2019LJ19 to Y.Z.)the Shanghai Rising-Star Program(22QA1401500 to X.H.)the Shanghai Committee of Science and Technology(21140902400 to Y.Z.,23ZR1407600,21ZR1410000 to F.J.and 20ZR1408300 to X.H.)the Shenzhen Science and Technology Peacock Team Project(KQTD20170331145453160)the National Health Research Institutes,Taiwan,China(EM-109-PP-10).
文摘Cytokine storms are crucial in the development of various inflammatory diseases,including sepsis and autoimmune disorders.The immunosuppressive cytokine INTERLEUKIN(IL)-37 consists of five isoforms(IL-37a-e).We identified IL-37a as a nuclear cytokine for the first time.Compared to IL-37b,IL-37a demonstrated greater efficacy in protecting against Toll-like receptor-induced cytokine hypersecretion and lethal endotoxic shock.The full-length(FL)form of IL-37a and the N-terminal fragment,which is processed by elastase,could translocate into cell nuclei through a distinctive nuclear localization sequence(NLS)/importin nuclear transport pathway.These forms exerted their regulatory effects independent of the IL-1R8 receptor by transcriptionally upregulating the nuclear receptor peroxisome proliferator-activated receptor(PPARγ).This process involved the recruitment of the H3K4 methyltransferase complex WDR5/MLL4/C/EBPβand H3K4me1/2 to the enhancer/promoter of Pparg.The receptor-independent regulatory pathway of the nuclear IL-37a–PPARγaxis and receptor-dependent signaling by secreted IL-37a maintain homeostasis and are potential therapeutic targets for various inflammatory diseases,including sepsis.
