Pub Date : 2024-12-16DOI: 10.1016/j.immuni.2024.11.017
Yinfeng Xu, Qian Wang, Jun Wang, Chuying Qian, Yusha Wang, Sheng Lu, Lijiang Song, Zhengfu He, Wei Liu, Wei Wan
Induction of autophagy is an ancient function of the cyclic GMP-AMP (cGAMP) synthase (cGAS)-stimulator of interferon genes (STING) pathway through which autophagic cargoes are delivered to lysosomes for degradation. However, whether lysosome function is also modulated by the cGAS-STING pathway remains unknown. Here, we discovered that the cGAS-STING pathway upregulated lysosomal activity by stimulating lysosome biogenesis independently of the downstream protein kinase TANK-binding kinase 1 (TBK1). STING activation enhanced lysosome biogenesis through inducing the nuclear translocation of transcription factor EB (TFEB) as well as its paralogs transcription factor E3 (TFE3) and microphthalmia-associated transcription factor (MITF). STING-induced lipidation of GABA type A receptor-associated protein (GABARAP), an autophagy-related protein, on STING vesicles was responsible for TFEB activation. Membrane-bound GABARAP sequestered the GTPase-activating protein folliculin (FLCN) and FLCN-interacting protein (FNIP) complex to block its function toward the Rag GTPases Ras-related GTP-binding C and D (RagC and RagD), abolishing mechanistic target of rapamycin (mTOR) complex 1 (mTORC1)-dependent phosphorylation and inactivation of TFEB. Functionally, STING-induced lysosome biogenesis within cells facilitated the clearance of cytoplasmic DNA and invading pathogens. Thus, our findings reveal that induction of lysosome biogenesis is another important function of the cGAS-STING pathway.
{"title":"The cGAS-STING pathway activates transcription factor TFEB to stimulate lysosome biogenesis and pathogen clearance","authors":"Yinfeng Xu, Qian Wang, Jun Wang, Chuying Qian, Yusha Wang, Sheng Lu, Lijiang Song, Zhengfu He, Wei Liu, Wei Wan","doi":"10.1016/j.immuni.2024.11.017","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.11.017","url":null,"abstract":"Induction of autophagy is an ancient function of the cyclic GMP-AMP (cGAMP) synthase (cGAS)-stimulator of interferon genes (STING) pathway through which autophagic cargoes are delivered to lysosomes for degradation. However, whether lysosome function is also modulated by the cGAS-STING pathway remains unknown. Here, we discovered that the cGAS-STING pathway upregulated lysosomal activity by stimulating lysosome biogenesis independently of the downstream protein kinase TANK-binding kinase 1 (TBK1). STING activation enhanced lysosome biogenesis through inducing the nuclear translocation of transcription factor EB (TFEB) as well as its paralogs transcription factor E3 (TFE3) and microphthalmia-associated transcription factor (MITF). STING-induced lipidation of GABA type A receptor-associated protein (GABARAP), an autophagy-related protein, on STING vesicles was responsible for TFEB activation. Membrane-bound GABARAP sequestered the GTPase-activating protein folliculin (FLCN) and FLCN-interacting protein (FNIP) complex to block its function toward the Rag GTPases Ras-related GTP-binding C and D (RagC and RagD), abolishing mechanistic target of rapamycin (mTOR) complex 1 (mTORC1)-dependent phosphorylation and inactivation of TFEB. Functionally, STING-induced lysosome biogenesis within cells facilitated the clearance of cytoplasmic DNA and invading pathogens. Thus, our findings reveal that induction of lysosome biogenesis is another important function of the cGAS-STING pathway.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"22 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142825551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-10DOI: 10.1016/j.immuni.2024.11.010
Wei-Wen Yu, Joy N.P. Barrett, Jie Tong, Meng-Ju Lin, Meaghan Marohn, Joseph C. Devlin, Alberto Herrera, Juliana Remark, Jamie Levine, Pei-Kang Liu, Victoria Fang, Abigail M. Zellmer, Derek A. Oldridge, E. John Wherry, Jia-Ren Lin, Jia-Yun Chen, Peter Sorger, Sandro Santagata, James G. Krueger, Kelly V. Ruggles, Catherine P. Lu
Hidradenitis suppurativa (HS) is a chronic, debilitating inflammatory skin disease characterized by keratinized epithelial tunnels that grow deeply into the dermis. Here, we examined the immune microenvironment within human HS lesions. Multi-omics profiling and multiplexed imaging identified tertiary lymphoid structures (TLSs) near HS tunnels. These TLSs were enriched with proliferative T cells, including follicular helper (Tfh), regulatory (Treg), and pathogenic T cells (IL17A+ and IFNG+), alongside extensive clonal expansion of plasma cells producing antibodies reactive to keratinocytes. HS fibroblasts express CXCL13 or CCL19 in response to immune cytokines. Using a microfluidic system to mimic TLS on a chip, we found that HS fibroblasts critically orchestrated lymphocyte aggregation via tumor necrosis factor alpha (TNF-α)-CXCL13 and TNF-α-CCL19 feedback loops with B and T cells, respectively; early TNF-α blockade suppressed aggregate initiation. Our findings provide insights into TLS formation in the skin, suggest therapeutic avenues for HS, and reveal mechanisms that may apply to other autoimmune settings, including Crohn’s disease.
{"title":"Skin immune-mesenchymal interplay within tertiarylymphoid structures promotes autoimmunepathogenesis in hidradenitis suppurativa","authors":"Wei-Wen Yu, Joy N.P. Barrett, Jie Tong, Meng-Ju Lin, Meaghan Marohn, Joseph C. Devlin, Alberto Herrera, Juliana Remark, Jamie Levine, Pei-Kang Liu, Victoria Fang, Abigail M. Zellmer, Derek A. Oldridge, E. John Wherry, Jia-Ren Lin, Jia-Yun Chen, Peter Sorger, Sandro Santagata, James G. Krueger, Kelly V. Ruggles, Catherine P. Lu","doi":"10.1016/j.immuni.2024.11.010","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.11.010","url":null,"abstract":"Hidradenitis suppurativa (HS) is a chronic, debilitating inflammatory skin disease characterized by keratinized epithelial tunnels that grow deeply into the dermis. Here, we examined the immune microenvironment within human HS lesions. Multi-omics profiling and multiplexed imaging identified tertiary lymphoid structures (TLSs) near HS tunnels. These TLSs were enriched with proliferative T cells, including follicular helper (Tfh), regulatory (Treg), and pathogenic T cells (<em>IL17A</em>+ and <em>IFNG</em>+), alongside extensive clonal expansion of plasma cells producing antibodies reactive to keratinocytes. HS fibroblasts express <em>CXCL13</em> or <em>CCL19</em> in response to immune cytokines. Using a microfluidic system to mimic TLS on a chip, we found that HS fibroblasts critically orchestrated lymphocyte aggregation via tumor necrosis factor alpha (TNF-α)-CXCL13 and TNF-α-CCL19 feedback loops with B and T cells, respectively; early TNF-α blockade suppressed aggregate initiation. Our findings provide insights into TLS formation in the skin, suggest therapeutic avenues for HS, and reveal mechanisms that may apply to other autoimmune settings, including Crohn’s disease.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"37 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142797596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-10DOI: 10.1016/j.immuni.2024.11.011
Cody Elkins, Chaoran Li
Hidradenitis suppurativa (HS) is a severe chronic inflammatory skin disease with limited response to therapy. In this issue of Immunity, Yu et al.1 identify skin tertiary lymphoid structures (TLSs) as primary sites for lymphocyte clonal expansion and autoantibody production, driving disease progression, and provide insight into how formation and maintenance of TLS impact therapeutic outcomes.
{"title":"Hidradenitis suppurativa: TLSs take the center stage","authors":"Cody Elkins, Chaoran Li","doi":"10.1016/j.immuni.2024.11.011","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.11.011","url":null,"abstract":"Hidradenitis suppurativa (HS) is a severe chronic inflammatory skin disease with limited response to therapy. In this issue of <em>Immunity</em>, Yu et al.<span><span><sup>1</sup></span></span> identify skin tertiary lymphoid structures (TLSs) as primary sites for lymphocyte clonal expansion and autoantibody production, driving disease progression, and provide insight into how formation and maintenance of TLS impact therapeutic outcomes.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"65 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142797532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-10DOI: 10.1016/j.immuni.2024.11.012
Kazuhiko Higashioka, Deepak A. Rao
Rheumatoid arthritis (RA) is driven by antigen-specific T cell responses targeting the joints. MacDonald et al.1 define the range of dendritic cell (DC) populations within joints of RA patients and highlight specific iDC3 and DC2 populations enriched in inflamed RA synovium that promote T cell activation as well as tolerogenic AXL+ DC2s in healthy synovium that are lost in RA.
{"title":"DC-T cell power couples in rheumatoid arthritis joints","authors":"Kazuhiko Higashioka, Deepak A. Rao","doi":"10.1016/j.immuni.2024.11.012","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.11.012","url":null,"abstract":"Rheumatoid arthritis (RA) is driven by antigen-specific T cell responses targeting the joints. MacDonald et al.<span><span><sup>1</sup></span></span> define the range of dendritic cell (DC) populations within joints of RA patients and highlight specific iDC3 and DC2 populations enriched in inflamed RA synovium that promote T cell activation as well as tolerogenic AXL<sup>+</sup> DC2s in healthy synovium that are lost in RA.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"13 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142797384","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-10DOI: 10.1016/j.immuni.2024.11.014
Andrew Y. Hu, Cristina Puig-Saus
Central tolerance restricts T cells that target self-antigens. In this issue of Immunity, Abdelfattah et al.1 describe a method to generate self-reactive T cell receptors (TCRs) by directed evolution of non-autoreactive TCRs to recognize self-antigen peptides and demonstrate potential for T cells engineered with such receptors in immunotherapy.
{"title":"T-switch-ing TCR specificity","authors":"Andrew Y. Hu, Cristina Puig-Saus","doi":"10.1016/j.immuni.2024.11.014","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.11.014","url":null,"abstract":"Central tolerance restricts T cells that target self-antigens. In this issue of <em>Immunity</em>, Abdelfattah et al.<span><span><sup>1</sup></span></span> describe a method to generate self-reactive T cell receptors (TCRs) by directed evolution of non-autoreactive TCRs to recognize self-antigen peptides and demonstrate potential for T cells engineered with such receptors in immunotherapy.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"44 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142797385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-10DOI: 10.1016/j.immuni.2024.11.016
Thomas Plum, Thorsten B. Feyerabend, Hans-Reimer Rodewald
Mast cells are regarded as effectors in immune defense against parasites and venoms and play an essential role in the pathology of allergic diseases. More recently, mast cells have been shown to receive stimuli derived from type 2 immunity, tissue damage, stress, and inflammation. Mast cells then rapidly convert these diverse signals into appropriate, organ-specific protective reflexes that can limit inflammation or reduce tissue damage. In this review, we consider functions of mast cells in sensations—such as pain, itch, and nausea—arising from tissue insults and inflammation and the ensuing protective responses. In light of emerging data highlighting the involvement of mast cells in neuroimmune communication, we also propose that mast cells are “signal converters” linking immunological and tissue states with nervous system responses.
{"title":"Beyond classical immunity: Mast cells as signal converters between tissues and neurons","authors":"Thomas Plum, Thorsten B. Feyerabend, Hans-Reimer Rodewald","doi":"10.1016/j.immuni.2024.11.016","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.11.016","url":null,"abstract":"Mast cells are regarded as effectors in immune defense against parasites and venoms and play an essential role in the pathology of allergic diseases. More recently, mast cells have been shown to receive stimuli derived from type 2 immunity, tissue damage, stress, and inflammation. Mast cells then rapidly convert these diverse signals into appropriate, organ-specific protective reflexes that can limit inflammation or reduce tissue damage. In this review, we consider functions of mast cells in sensations—such as pain, itch, and nausea—arising from tissue insults and inflammation and the ensuing protective responses. In light of emerging data highlighting the involvement of mast cells in neuroimmune communication, we also propose that mast cells are “signal converters” linking immunological and tissue states with nervous system responses.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"97 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142797533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-10DOI: 10.1016/j.immuni.2024.11.015
Shilpi Giri, Amanda C. Poholek
Despite protective roles in various type of infection and in would healing, T helper (Th)2 cells are drivers of inflammation in allergic asthma. In this issue of Immunity, Zou et al. demonstrate the crucial involvement of hypoxia inducible factor (HIF)2α in promoting the differentiation of inflammatory Th2 cells, suggesting HIF2α as a promising therapeutic target for the treatment of allergic asthma.
{"title":"Gasping for air: HIF2α in asthma","authors":"Shilpi Giri, Amanda C. Poholek","doi":"10.1016/j.immuni.2024.11.015","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.11.015","url":null,"abstract":"Despite protective roles in various type of infection and in would healing, T helper (Th)2 cells are drivers of inflammation in allergic asthma. In this issue of <em>Immunity</em>, Zou et al. demonstrate the crucial involvement of hypoxia inducible factor (HIF)2α in promoting the differentiation of inflammatory Th2 cells, suggesting HIF2α as a promising therapeutic target for the treatment of allergic asthma.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"8 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142797531","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-10DOI: 10.1016/j.immuni.2024.11.013
Camille A. Spinner, Vanja Lazarevic
CD4+ T helper (Th) cell differentiation depends on regulatory networks that enforce lineage commitment while suppressing alternative fates. In a recent issue of Nature, Hou et al. reveal that calcitonin gene-related peptide (CGRP) directs Th1 commitment, highlighting neuro-immune crosstalk in T cell fate decisions.
{"title":"Getting RAMPed up: Neuropeptides boost T helper 1 cell fate","authors":"Camille A. Spinner, Vanja Lazarevic","doi":"10.1016/j.immuni.2024.11.013","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.11.013","url":null,"abstract":"CD4<sup>+</sup> T helper (Th) cell differentiation depends on regulatory networks that enforce lineage commitment while suppressing alternative fates. In a recent issue of <em>Nature</em>, Hou et al. reveal that calcitonin gene-related peptide (CGRP) directs Th1 commitment, highlighting neuro-immune crosstalk in T cell fate decisions.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"20 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142797304","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-09DOI: 10.1016/j.immuni.2024.11.003
Alessandro Matera, Anne-Claire Compagnion, Chiara Pedicone, M. Kotah Janssen, Andranik Ivanov, Katia Monsorno, Gwenaël Labouèbe, Loredana Leggio, Marta Pereira, Dieter Beule, Virginie Mansuy-Aubert, Tim L. Williams, Nunzio Iraci, Amanda Sierra, Samuele G. Marro, Alison M. Goate, Bart J.L. Eggen, William G. Kerr, Rosa C. Paolicelli
The gene inositol polyphosphate-5-phosphatase D (INPP5D), which encodes the lipid phosphatase SH2-containing inositol polyphosphate 5-phosphatase 1 (SHIP1), is associated with the risk of Alzheimer’s disease (AD). How it influences microglial function and brain physiology is unclear. Here, we showed that SHIP1 was enriched in early stages of healthy brain development. By combining in vivo loss-of-function approaches and proteomics, we discovered that mice conditionally lacking microglial SHIP1 displayed increased complement and synapse loss in the early postnatal brain. SHIP1-deficient microglia showed altered transcriptional signatures and abnormal synaptic pruning that was dependent on the complement system. Mice exhibited cognitive defects in adulthood only when microglial SHIP1 was depleted early postnatally but not at later stages. Induced pluripotent stem cell (iPSC)-derived microglia lacking SHIP1 also showed increased engulfment of synaptic structures. These findings suggest that SHIP1 is essential for proper microglia-mediated synapse remodeling in the healthy developing brain. Disrupting this process has lasting behavioral effects and may be linked to vulnerability to neurodegeneration.
{"title":"Microglial lipid phosphatase SHIP1 limits complement-mediated synaptic pruning in the healthy developing hippocampus","authors":"Alessandro Matera, Anne-Claire Compagnion, Chiara Pedicone, M. Kotah Janssen, Andranik Ivanov, Katia Monsorno, Gwenaël Labouèbe, Loredana Leggio, Marta Pereira, Dieter Beule, Virginie Mansuy-Aubert, Tim L. Williams, Nunzio Iraci, Amanda Sierra, Samuele G. Marro, Alison M. Goate, Bart J.L. Eggen, William G. Kerr, Rosa C. Paolicelli","doi":"10.1016/j.immuni.2024.11.003","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.11.003","url":null,"abstract":"The gene inositol polyphosphate-5-phosphatase D (<em>INPP5D</em>), which encodes the lipid phosphatase SH2-containing inositol polyphosphate 5-phosphatase 1 (SHIP1), is associated with the risk of Alzheimer’s disease (AD). How it influences microglial function and brain physiology is unclear. Here, we showed that SHIP1 was enriched in early stages of healthy brain development. By combining <em>in vivo</em> loss-of-function approaches and proteomics, we discovered that mice conditionally lacking microglial SHIP1 displayed increased complement and synapse loss in the early postnatal brain. SHIP1-deficient microglia showed altered transcriptional signatures and abnormal synaptic pruning that was dependent on the complement system. Mice exhibited cognitive defects in adulthood only when microglial SHIP1 was depleted early postnatally but not at later stages. Induced pluripotent stem cell (iPSC)-derived microglia lacking SHIP1 also showed increased engulfment of synaptic structures. These findings suggest that SHIP1 is essential for proper microglia-mediated synapse remodeling in the healthy developing brain. Disrupting this process has lasting behavioral effects and may be linked to vulnerability to neurodegeneration.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"37 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142793587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-06DOI: 10.1016/j.immuni.2024.11.008
Mengyu Xia, Junmei Lu, Jiabin Lan, Teng Teng, Rani Shiao, Hongbin Sun, Zheyu Jin, Xueer Liu, Jie Wang, Hongyan Wu, Changchun Wang, Han Yi, Qingqing Qi, Jixi Li, Marc Schneeberger, Wei Shen, Boxun Lu, Lei Chen, Anoj Ilanges, Xinyu Zhou, Xiaofei Yu
Psychological stress and its sequelae pose a major challenge to public health. Immune activation is conventionally thought to aggravate stress-related mental diseases such as anxiety disorders and depression. Here, we sought to identify potentially beneficial consequences of immune activation in response to stress. We showed that stress led to increased interleukin (IL)-22 production in the intestine as a result of stress-induced gut leakage. IL-22 was both necessary and sufficient to attenuate stress-induced anxiety behaviors in mice. More specifically, IL-22 gained access to the septal area of the brain and directly suppressed neuron activation. Furthermore, human patients with clinical depression displayed reduced IL-22 levels, and exogenous IL-22 treatment ameliorated depressive-like behavior elicited by chronic stress in mice. Our study thus identifies a gut-brain axis in response to stress, whereby IL-22 reduces neuronal activation and concomitant anxiety behavior, suggesting that early immune activation can provide protection against psychological stress.
{"title":"Elevated IL-22 as a result of stress-induced gut leakage suppresses septal neuron activation to ameliorate anxiety-like behavior","authors":"Mengyu Xia, Junmei Lu, Jiabin Lan, Teng Teng, Rani Shiao, Hongbin Sun, Zheyu Jin, Xueer Liu, Jie Wang, Hongyan Wu, Changchun Wang, Han Yi, Qingqing Qi, Jixi Li, Marc Schneeberger, Wei Shen, Boxun Lu, Lei Chen, Anoj Ilanges, Xinyu Zhou, Xiaofei Yu","doi":"10.1016/j.immuni.2024.11.008","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.11.008","url":null,"abstract":"Psychological stress and its sequelae pose a major challenge to public health. Immune activation is conventionally thought to aggravate stress-related mental diseases such as anxiety disorders and depression. Here, we sought to identify potentially beneficial consequences of immune activation in response to stress. We showed that stress led to increased interleukin (IL)-22 production in the intestine as a result of stress-induced gut leakage. IL-22 was both necessary and sufficient to attenuate stress-induced anxiety behaviors in mice. More specifically, IL-22 gained access to the septal area of the brain and directly suppressed neuron activation. Furthermore, human patients with clinical depression displayed reduced IL-22 levels, and exogenous IL-22 treatment ameliorated depressive-like behavior elicited by chronic stress in mice. Our study thus identifies a gut-brain axis in response to stress, whereby IL-22 reduces neuronal activation and concomitant anxiety behavior, suggesting that early immune activation can provide protection against psychological stress.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"8 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142782541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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