Pub Date : 2024-11-08DOI: 10.1016/j.mucimm.2024.11.002
Nai-Wen Fan, Man Yu, Shudan Wang, Tomas Blanco, Zala Luznik, Sunil K Chauhan, Veena Viswanath, Daniel Gil, Katherine Held, Yihe Chen, Reza Dana
There is an unmet need for effectively treating dry eye disease (DED), a T cell-mediated chronic, inflammatory ocular surface disorder. Given the potential of nonneuronal adrenergic system in modulating T cell response, we herein investigated the therapeutic efficacy and the underlying mechanisms of a specific alpha 2 adrenergic receptor agonist (AGN-762, selective for α2B/2C receptor subtypes) in a mouse model of DED. Experimental DED was treated with the AGN-762 by oral gavage, either at disease induction or after disease establishment, and showed sustained amelioration, along with reduced expression of DED-pathogenic cytokines in ocular surface tissues, decreased corneal MHC-II+CD11b+ cells and lymphoid Th17 cells, and higher function of regulatory T cells (Treg). In vitro culture of DED-derived effector T helper cells (Teff) with AGN-762 failed to suppress Th17 response, while culture of DED-Treg with AGN-762 led to enhanced suppressive function of Treg and their IL-10 production. Adoptive transfer of AGN-762-pretreated DED-Treg in syngeneic B6.Rag1-/- mice effectively suppressed DED Teff-mediated disease and Th17 response, and the effect was abolished by the neutralization of IL-10. In conclusion, our findings demonstrate that α2B/2C adrenergic receptor agonism effectively ameliorates persistent corneal epitheliopathy in DED by enhancing IL-10 production from Treg and thus restoring their immunoregulatory function.
干眼症(DED)是一种由 T 细胞介导的慢性、炎症性眼表疾病,有效治疗干眼症的需求尚未得到满足。鉴于非神经元肾上腺素能系统在调节 T 细胞反应方面的潜力,我们在此研究了特异性α2 肾上腺素能受体激动剂(AGN-762,对α2B/2C 受体亚型具有选择性)在 DED 小鼠模型中的疗效及其潜在机制。实验性 DED 在疾病诱导期或发病后通过口服 AGN-762 治疗,结果显示病情持续改善,眼表组织中 DED 致病细胞因子的表达减少,角膜 MHC-II+CD11b+ 细胞和淋巴 Th17 细胞减少,调节性 T 细胞(Treg)的功能增强。用 AGN-762 体外培养 DED 衍生的效应 T 辅助细胞 (Teff) 未能抑制 Th17 反应,而用 AGN-762 培养 DED-Treg 则增强了 Treg 的抑制功能及其 IL-10 的产生。AGN-762预处理过的DED-Treg在共生B6.Rag1-/-小鼠中的接种转移能有效抑制DED Teff介导的疾病和Th17反应,而IL-10的中和作用会取消这种效果。总之,我们的研究结果表明,α2B/2C肾上腺素能受体激动能通过增强Treg产生IL-10从而恢复其免疫调节功能,从而有效地改善DED的持续性角膜上皮病变。
{"title":"Activation of α2B/2C adrenergic receptor ameliorates ocular surface inflammation through enhancing regulatory T cell function.","authors":"Nai-Wen Fan, Man Yu, Shudan Wang, Tomas Blanco, Zala Luznik, Sunil K Chauhan, Veena Viswanath, Daniel Gil, Katherine Held, Yihe Chen, Reza Dana","doi":"10.1016/j.mucimm.2024.11.002","DOIUrl":"https://doi.org/10.1016/j.mucimm.2024.11.002","url":null,"abstract":"<p><p>There is an unmet need for effectively treating dry eye disease (DED), a T cell-mediated chronic, inflammatory ocular surface disorder. Given the potential of nonneuronal adrenergic system in modulating T cell response, we herein investigated the therapeutic efficacy and the underlying mechanisms of a specific alpha 2 adrenergic receptor agonist (AGN-762, selective for α2B/2C receptor subtypes) in a mouse model of DED. Experimental DED was treated with the AGN-762 by oral gavage, either at disease induction or after disease establishment, and showed sustained amelioration, along with reduced expression of DED-pathogenic cytokines in ocular surface tissues, decreased corneal MHC-II<sup>+</sup>CD11b<sup>+</sup> cells and lymphoid Th17 cells, and higher function of regulatory T cells (Treg). In vitro culture of DED-derived effector T helper cells (Teff) with AGN-762 failed to suppress Th17 response, while culture of DED-Treg with AGN-762 led to enhanced suppressive function of Treg and their IL-10 production. Adoptive transfer of AGN-762-pretreated DED-Treg in syngeneic B6.Rag1<sup>-/-</sup> mice effectively suppressed DED Teff-mediated disease and Th17 response, and the effect was abolished by the neutralization of IL-10. In conclusion, our findings demonstrate that α2B/2C adrenergic receptor agonism effectively ameliorates persistent corneal epitheliopathy in DED by enhancing IL-10 production from Treg and thus restoring their immunoregulatory function.</p>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142622789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-07DOI: 10.1016/j.mucimm.2024.11.001
Cristina M Chiarolla, Axel R Schulz, Michael Meir, Sebastian Ferrara, Yin Xiao, Simone Reu-Hofer, Addi J Romero-Olmedo, Valeria Falcone, Katja Hoffmann, Maike Büttner-Herold, Martina Prelog, Andreas Rosenwald, Hartmut Hengel, Michael Lohoff, Hyun-Dong Chang, Nicolas Schlegel, Henrik E Mei, Friederike Berberich-Siebelt
Altered intestinal immune homeostasis leads to chronic inflammation in Crohn's disease (CD). To address disease- and tissue-specific alterations, we performed a T cell-centric mass cytometry analysis of peripheral and intestinal lymphocytes from patients with CD and healthy donors' PBMCs. Chronic intestinal inflammation enforced activation, exhaustion, and terminal differentiation of CD4+ and CD8+ T cells and a relative enrichment of CD4+ regulatory T (Treg) cells. Moreover, enigmatic rare Treg subsets appeared upon inflammation, e.g. CD4+FOXP3+HLA-DR+TIGIT- and CD4+FOXP3+CD56+, expressing pro-inflammatory IFN-γ upon in vitro stimulation. Some conventional T (Tcon) cells acquired NK-like features. In CD patients' blood, not well studied CD16+CCR6+CD127+ T cells appeared, being CD4+ or CD8+, a phenotype inducible on healthy T cells by CD blood plasma. Upon CD16-mediated antibody binding, they could attain effector function. These findings suggest an uncommon pro-inflammatory innate-like differentiation of Treg and Tcon cells with acquisition of non-specific cytotoxicity. Most likely, this is both cause and consequence of intestinal inflammation during CD.
肠道免疫平衡的改变导致了克罗恩病(CD)的慢性炎症。针对疾病和组织特异性改变,我们对克罗恩病患者的外周和肠道淋巴细胞以及健康供体的 PBMCs 进行了以 T 细胞为中心的质谱分析。慢性肠道炎症导致 CD4+ 和 CD8+ T 细胞活化、衰竭和终末分化,CD4+ 调节性 T(Treg)细胞相对富集。此外,炎症时还会出现神秘的稀有 Treg 亚群,如 CD4+FOXP3+HLA-DR+TIGIT- 和 CD4+FOXP3+CD56+,体外刺激时可表达促炎性 IFN-γ。一些常规 T(Tcon)细胞具有类似 NK 的特征。在 CD 患者的血液中,出现了研究不多的 CD16+CCR6+CD127+ T 细胞,它们是 CD4+ 或 CD8+,这是 CD 血浆在健康 T 细胞上诱导的表型。在 CD16 介导的抗体结合后,它们可以获得效应功能。这些研究结果表明,Treg 和 Tcon 细胞具有不常见的促炎症先天性样分化,并获得非特异性细胞毒性。这很可能是 CD 期间肠道炎症的原因和结果。
{"title":"Pro-inflammatory NK-like T cells are expanded in the blood and inflamed intestine in Crohn's disease.","authors":"Cristina M Chiarolla, Axel R Schulz, Michael Meir, Sebastian Ferrara, Yin Xiao, Simone Reu-Hofer, Addi J Romero-Olmedo, Valeria Falcone, Katja Hoffmann, Maike Büttner-Herold, Martina Prelog, Andreas Rosenwald, Hartmut Hengel, Michael Lohoff, Hyun-Dong Chang, Nicolas Schlegel, Henrik E Mei, Friederike Berberich-Siebelt","doi":"10.1016/j.mucimm.2024.11.001","DOIUrl":"https://doi.org/10.1016/j.mucimm.2024.11.001","url":null,"abstract":"<p><p>Altered intestinal immune homeostasis leads to chronic inflammation in Crohn's disease (CD). To address disease- and tissue-specific alterations, we performed a T cell-centric mass cytometry analysis of peripheral and intestinal lymphocytes from patients with CD and healthy donors' PBMCs. Chronic intestinal inflammation enforced activation, exhaustion, and terminal differentiation of CD4<sup>+</sup> and CD8<sup>+</sup> T cells and a relative enrichment of CD4<sup>+</sup> regulatory T (Treg) cells. Moreover, enigmatic rare Treg subsets appeared upon inflammation, e.g. CD4<sup>+</sup>FOXP3<sup>+</sup>HLA-DR<sup>+</sup>TIGIT<sup>-</sup> and CD4<sup>+</sup>FOXP3<sup>+</sup>CD56<sup>+</sup>, expressing pro-inflammatory IFN-γ upon in vitro stimulation. Some conventional T (Tcon) cells acquired NK-like features. In CD patients' blood, not well studied CD16<sup>+</sup>CCR6<sup>+</sup>CD127<sup>+</sup> T cells appeared, being CD4<sup>+</sup> or CD8<sup>+</sup>, a phenotype inducible on healthy T cells by CD blood plasma. Upon CD16-mediated antibody binding, they could attain effector function. These findings suggest an uncommon pro-inflammatory innate-like differentiation of Treg and Tcon cells with acquisition of non-specific cytotoxicity. Most likely, this is both cause and consequence of intestinal inflammation during CD.</p>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142623077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-18DOI: 10.1016/j.mucimm.2024.10.002
Gesa J Albers, Christina Michalaki, Patricia P Ogger, Amy F Lloyd, Benjamin Causton, Simone A Walker, Anna Caldwell, John M Halket, Linda V Sinclair, Sarah H Forde, Cormac McCarthy, Timothy S C Hinks, Clare M Lloyd, Adam J Byrne
The lungs represent a dynamic microenvironment where airway macrophages (AMs) are the major lung-resident macrophages. AMs dictate the balance between tissue homeostasis and immune activation and thus have contradictory functions by maintaining tolerance and tissue homeostasis, as well as initiating strong inflammatory responses. Emerging evidence has highlighted the connection between macrophage function and cellular metabolism. However, the functional importance of these processes in tissue-resident specialized macrophage populations such as those found in the airways, remain poorly elucidated. Here, we reveal that glycolysis is a fundamental pathway in AMs which regulates both lung homeostasis and responses to inhaled allergen. Using macrophage specific targeting in vivo, and multi-omics approaches, we determined that glycolytic activity in AMs is necessary to restrain type 2 (T2) immunity during homeostasis. Exposure to a range of common aeroallergens, including house dust mite (HDM), drove AM-glycolysis and furthermore, AM-specific inhibition of glycolysis altered inflammation in the airways and HDM-driven airway metabolic adaptations in vivo. Additionally, allergen sensitised asthmatics had profound metabolic changes in the airways, compared to non-sensitised asthmatic controls. Finally, we found that allergen driven AM-glycolysis in mice was TLR2 dependent. Thus, our findings demonstrate a direct relationship between glycolysis in AMs, AM-mediated homeostatic processes, and T2 immune responses in the lungs. These data suggest that glycolysis is essential for the plasticity of AMs. Depending on the immunological context, AM-glycolysis is required to exert homeostatic activity but once activated by allergen, AM-glycolysis influences inflammatory responses. Thus, precise modulation of glycolytic activity in AMs is essential for preserving lung homeostasis and regulating airway inflammation.
肺是一个动态的微环境,气道巨噬细胞(AMs)是驻肺的主要巨噬细胞。巨噬细胞决定着组织稳态和免疫激活之间的平衡,因此具有相互矛盾的功能,既能维持耐受性和组织稳态,又能引发强烈的炎症反应。新的证据强调了巨噬细胞功能与细胞新陈代谢之间的联系。然而,这些过程在组织驻留的特化巨噬细胞群(如在呼吸道中发现的巨噬细胞群)中的功能重要性仍未得到充分阐明。在这里,我们揭示了糖酵解是巨噬细胞的一个基本途径,它同时调节着肺的稳态和对吸入过敏原的反应。利用体内巨噬细胞特异性靶向和多组学方法,我们确定了AMs中的糖酵解活性是在体内平衡过程中抑制2型(T2)免疫所必需的。暴露于包括屋尘螨(HDM)在内的一系列常见空气过敏原会促进AM糖酵解,此外,AM特异性糖酵解抑制会改变气道炎症和HDM驱动的体内气道代谢适应。此外,与未致敏的哮喘对照组相比,过敏原致敏的哮喘患者的气道代谢发生了深刻变化。最后,我们发现过敏原驱动的小鼠 AM 糖酵解作用依赖于 TLR2。因此,我们的研究结果表明,AM 中的糖酵解、AM 介导的体内平衡过程和肺部的 T2 免疫反应之间存在直接关系。这些数据表明,糖酵解对 AM 的可塑性至关重要。根据不同的免疫环境,AM-糖酵解需要发挥稳态活性,但一旦被过敏原激活,AM-糖酵解就会影响炎症反应。因此,精确调节AMs中的糖酵解活性对于保持肺稳态和调节气道炎症至关重要。
{"title":"Airway macrophage glycolysis controls lung homeostasis and responses to aeroallergen.","authors":"Gesa J Albers, Christina Michalaki, Patricia P Ogger, Amy F Lloyd, Benjamin Causton, Simone A Walker, Anna Caldwell, John M Halket, Linda V Sinclair, Sarah H Forde, Cormac McCarthy, Timothy S C Hinks, Clare M Lloyd, Adam J Byrne","doi":"10.1016/j.mucimm.2024.10.002","DOIUrl":"10.1016/j.mucimm.2024.10.002","url":null,"abstract":"<p><p>The lungs represent a dynamic microenvironment where airway macrophages (AMs) are the major lung-resident macrophages. AMs dictate the balance between tissue homeostasis and immune activation and thus have contradictory functions by maintaining tolerance and tissue homeostasis, as well as initiating strong inflammatory responses. Emerging evidence has highlighted the connection between macrophage function and cellular metabolism. However, the functional importance of these processes in tissue-resident specialized macrophage populations such as those found in the airways, remain poorly elucidated. Here, we reveal that glycolysis is a fundamental pathway in AMs which regulates both lung homeostasis and responses to inhaled allergen. Using macrophage specific targeting in vivo, and multi-omics approaches, we determined that glycolytic activity in AMs is necessary to restrain type 2 (T2) immunity during homeostasis. Exposure to a range of common aeroallergens, including house dust mite (HDM), drove AM-glycolysis and furthermore, AM-specific inhibition of glycolysis altered inflammation in the airways and HDM-driven airway metabolic adaptations in vivo. Additionally, allergen sensitised asthmatics had profound metabolic changes in the airways, compared to non-sensitised asthmatic controls. Finally, we found that allergen driven AM-glycolysis in mice was TLR2 dependent. Thus, our findings demonstrate a direct relationship between glycolysis in AMs, AM-mediated homeostatic processes, and T2 immune responses in the lungs. These data suggest that glycolysis is essential for the plasticity of AMs. Depending on the immunological context, AM-glycolysis is required to exert homeostatic activity but once activated by allergen, AM-glycolysis influences inflammatory responses. Thus, precise modulation of glycolytic activity in AMs is essential for preserving lung homeostasis and regulating airway inflammation.</p>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470338","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
To establish protection against harmful foreign antigens, the small intestine harbors guardian sites called Peyer's patches (PPs). PPs take up antigens through microfold (M) cells and transfer them to the sub-epithelial dome (SED), which contains a high density of mononuclear phagocytes (MPs), for T cell-priming. Accumulating evidence indicates that SED-MPs have unique functions other than T cell-priming to facilitate mucosal immune responses; however, the crucial factors regulating the functions of SED-MPs have not been determined. Here we performed transcriptome analysis, and identified the gene signatures of SED-MPs. Further data interpretation with transcription factor (TF) enrichment analysis estimated TFs responsible for the functions of SED-MPs. Among them, we found that RelB and C/EBPα were preferentially activated in SED-MPs. RelB-deficiency silenced the expression of IL-22BP and S100A4 by SED-MPs. On the other hand, C/EBPα-deficiency decreased the expression of lysozyme by SED-MPs, resulting the increased invasion of orally administered pathogenic bacteria into PPs and mesenteric lymph nodes. Our findings thus demonstrate that RelB and C/EBPα are essential to regulate the functions of SED-MPs.
{"title":"RelB and C/EBPα critically regulate the development of Peyer's patch mononuclear phagocytes.","authors":"Takashi Kanaya, Toshi Jinnohara, Sayuri Sakakibara, Naoko Tachibana, Takaharu Sasaki, Tamotsu Kato, Marc Riemann, Jianshi Jin, Katsuyuki Shiroguchi, Eiryo Kawakami, Hiroshi Ohno","doi":"10.1016/j.mucimm.2024.10.005","DOIUrl":"https://doi.org/10.1016/j.mucimm.2024.10.005","url":null,"abstract":"<p><p>To establish protection against harmful foreign antigens, the small intestine harbors guardian sites called Peyer's patches (PPs). PPs take up antigens through microfold (M) cells and transfer them to the sub-epithelial dome (SED), which contains a high density of mononuclear phagocytes (MPs), for T cell-priming. Accumulating evidence indicates that SED-MPs have unique functions other than T cell-priming to facilitate mucosal immune responses; however, the crucial factors regulating the functions of SED-MPs have not been determined. Here we performed transcriptome analysis, and identified the gene signatures of SED-MPs. Further data interpretation with transcription factor (TF) enrichment analysis estimated TFs responsible for the functions of SED-MPs. Among them, we found that RelB and C/EBPα were preferentially activated in SED-MPs. RelB-deficiency silenced the expression of IL-22BP and S100A4 by SED-MPs. On the other hand, C/EBPα-deficiency decreased the expression of lysozyme by SED-MPs, resulting the increased invasion of orally administered pathogenic bacteria into PPs and mesenteric lymph nodes. Our findings thus demonstrate that RelB and C/EBPα are essential to regulate the functions of SED-MPs.</p>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Infections by enteric virus and intestinal inflammation are recognized as a leading cause of deadly gastroenteritis, and NLRP6 and NLRP9b signaling control these infection and inflammation. However, the regulatory mechanisms of the NLRP6 and NLRP9b signaling in enteric viral infection remain unexplored. In this study, we found that the E3 ligase TRIM29 suppressed type III interferon (IFN-λ) and interleukin-18 (IL-18) production by intestinal epithelial cells (IECs) when exposed to polyinosinic:polycytidylic acid (poly I:C) and enteric RNA viruses. Knockout of TRIM29 in IECs was efficient to restrict intestinal inflammation triggered by the enteric RNA viruses, rotavirus in suckling mice, and the encephalomyocarditis virus (EMCV) in adults. This attenuation in inflammation was attributed to the increased production of IFN-λ and IL-18 in the IECs and more recruitment of intraepithelial protective Ly6A+CCR9+CD4+ T cells in small intestines from TRIM29-deficient mice. Mechanistically, TRIM29 promoted K48-linked ubiquitination, leading to the degradation of NLRP6 and NLRP9b, resulting in decreased IFN-λ and IL-18 secretion by IECs. Our findings reveal that enteric viruses utilize TRIM29 to inhibit IFN-λ and inflammasome activation in IECs, thereby facilitating viral-induced intestinal inflammation. This indicates that targeting TRIM29 could offer a promising therapeutic strategy for alleviating gut diseases.
{"title":"TRIM29 controls enteric RNA virus-induced intestinal inflammation by targeting NLRP6 and NLRP9b signaling pathways.","authors":"Junying Wang, Ling Wang, Wenting Lu, Naser Farhataziz, Anastasia Gonzalez, Junji Xing, Zhiqiang Zhang","doi":"10.1016/j.mucimm.2024.10.004","DOIUrl":"10.1016/j.mucimm.2024.10.004","url":null,"abstract":"<p><p>Infections by enteric virus and intestinal inflammation are recognized as a leading cause of deadly gastroenteritis, and NLRP6 and NLRP9b signaling control these infection and inflammation. However, the regulatory mechanisms of the NLRP6 and NLRP9b signaling in enteric viral infection remain unexplored. In this study, we found that the E3 ligase TRIM29 suppressed type III interferon (IFN-λ) and interleukin-18 (IL-18) production by intestinal epithelial cells (IECs) when exposed to polyinosinic:polycytidylic acid (poly I:C) and enteric RNA viruses. Knockout of TRIM29 in IECs was efficient to restrict intestinal inflammation triggered by the enteric RNA viruses, rotavirus in suckling mice, and the encephalomyocarditis virus (EMCV) in adults. This attenuation in inflammation was attributed to the increased production of IFN-λ and IL-18 in the IECs and more recruitment of intraepithelial protective Ly6A<sup>+</sup>CCR9<sup>+</sup>CD4<sup>+</sup> T cells in small intestines from TRIM29-deficient mice. Mechanistically, TRIM29 promoted K48-linked ubiquitination, leading to the degradation of NLRP6 and NLRP9b, resulting in decreased IFN-λ and IL-18 secretion by IECs. Our findings reveal that enteric viruses utilize TRIM29 to inhibit IFN-λ and inflammasome activation in IECs, thereby facilitating viral-induced intestinal inflammation. This indicates that targeting TRIM29 could offer a promising therapeutic strategy for alleviating gut diseases.</p>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-09DOI: 10.1016/j.mucimm.2024.10.003
Fabian Bick, Christophe Blanchetot, Bart N Lambrecht, Martijn J Schuijs
While much is known about the functional effects of type 2 cytokines interleukin (IL)-4, IL-5 and IL-13 in homeostasis and disease, we still poorly understand the functions of IL-9. Chronic inflammation seen in allergic diseases, autoimmunity and cancer is however frequently accompanied by overproduction of this elusive type 2 cytokine. Initially identified as a T cell and mast cell growth factor, and later as the hallmark cytokine defining TH9 cells, we now know that IL-9 is produced by multiple innate and adaptive immune cells. Recent evidence suggests that IL-9 controls discrete aspects of the allergic cascade, cellular responses of immune and stromal cells, cancer progression, tolerance and immune escape. Despite functioning as a pleiotropic cytokine in mucosal environments, like the lungs, the direct and indirect cellular targets of IL-9 are still not well characterized. Here, we discuss IL-9's cellular senders and receivers, focusing on asthma and cancer. Moreover, we review current research directions and the outlook of targeted therapy centered around the biology of IL-9.
{"title":"A reappraisal of IL-9 in inflammation and cancer.","authors":"Fabian Bick, Christophe Blanchetot, Bart N Lambrecht, Martijn J Schuijs","doi":"10.1016/j.mucimm.2024.10.003","DOIUrl":"10.1016/j.mucimm.2024.10.003","url":null,"abstract":"<p><p>While much is known about the functional effects of type 2 cytokines interleukin (IL)-4, IL-5 and IL-13 in homeostasis and disease, we still poorly understand the functions of IL-9. Chronic inflammation seen in allergic diseases, autoimmunity and cancer is however frequently accompanied by overproduction of this elusive type 2 cytokine. Initially identified as a T cell and mast cell growth factor, and later as the hallmark cytokine defining T<sub>H</sub>9 cells, we now know that IL-9 is produced by multiple innate and adaptive immune cells. Recent evidence suggests that IL-9 controls discrete aspects of the allergic cascade, cellular responses of immune and stromal cells, cancer progression, tolerance and immune escape. Despite functioning as a pleiotropic cytokine in mucosal environments, like the lungs, the direct and indirect cellular targets of IL-9 are still not well characterized. Here, we discuss IL-9's cellular senders and receivers, focusing on asthma and cancer. Moreover, we review current research directions and the outlook of targeted therapy centered around the biology of IL-9.</p>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142400786","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-05DOI: 10.1016/j.mucimm.2024.10.001
Zhen Wang, Keaton Song, Brian S Kim, John Manion
Epithelial barriers such as the skin, lung, and gut, in addition to having unique physiologic functions, are designed to preserve tissue homeostasis upon challenge with a variety of allergens, irritants, or pathogens. Both the innate and adaptive immune systems play a critical role in responding to epithelial cues triggered by environmental stimuli. However, the mechanisms by which organs sense and coordinate complex epithelial, stromal, and immune responses have remained a mystery. Our increasing understanding of the anatomic and functional characteristics of the sensory nervous system is greatly advancing a new field of peripheral neuroimmunology and subsequently changing our understanding of mucosal immunology. Herein, we detail how sensory biology is informing mucosal neuroimmunology, even beyond neuroimmune interactions seen within the central and autonomic nervous systems.
{"title":"Sensory neuroimmune interactions at the barrier.","authors":"Zhen Wang, Keaton Song, Brian S Kim, John Manion","doi":"10.1016/j.mucimm.2024.10.001","DOIUrl":"10.1016/j.mucimm.2024.10.001","url":null,"abstract":"<p><p>Epithelial barriers such as the skin, lung, and gut, in addition to having unique physiologic functions, are designed to preserve tissue homeostasis upon challenge with a variety of allergens, irritants, or pathogens. Both the innate and adaptive immune systems play a critical role in responding to epithelial cues triggered by environmental stimuli. However, the mechanisms by which organs sense and coordinate complex epithelial, stromal, and immune responses have remained a mystery. Our increasing understanding of the anatomic and functional characteristics of the sensory nervous system is greatly advancing a new field of peripheral neuroimmunology and subsequently changing our understanding of mucosal immunology. Herein, we detail how sensory biology is informing mucosal neuroimmunology, even beyond neuroimmune interactions seen within the central and autonomic nervous systems.</p>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142391831","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.mucimm.2024.07.004
Joanne E. Konkel, Joshua R. Cox, Kelly Wemyss
Immune cells residing at the gingiva experience diverse and unique signals, tailoring their functions to enable them to appropriately respond to immunological challenges and maintain tissue integrity. The gingiva, defined as the mucosal barrier that surrounds and supports the teeth, is the only barrier site completely transected by a hard structure, the tooth. The tissue is damaged in early life during tooth eruption and chronically throughout life by the process of mastication. This occurs alongside challenges typical of barrier sites, including exposure to invading pathogens, the local commensal microbial community and environmental antigens. This review will focus on the immune network safeguarding gingival integrity, which is far less understood than that resident at other barrier sites. A detailed understanding of the gingiva-resident immune network is vital as it is the site of the inflammatory disease periodontitis, the most common chronic inflammatory condition in humans which has well-known detrimental systemic effects. Furthering our understanding of how the immune populations within the gingiva develop, are tailored in health, and how this is dysregulated in disease would further the development of effective therapies for periodontitis.
{"title":"Bite-sized immunology; damage and microbes educating immunity at the gingiva","authors":"Joanne E. Konkel, Joshua R. Cox, Kelly Wemyss","doi":"10.1016/j.mucimm.2024.07.004","DOIUrl":"10.1016/j.mucimm.2024.07.004","url":null,"abstract":"<div><div>Immune cells residing at the gingiva experience diverse and unique signals, tailoring their functions to enable them to appropriately respond to immunological challenges and maintain tissue integrity. The gingiva, defined as the mucosal barrier that surrounds and supports the teeth, is the only barrier site completely transected by a hard structure, the tooth. The tissue is damaged in early life during tooth eruption and chronically throughout life by the process of mastication. This occurs alongside challenges typical of barrier sites, including exposure to invading pathogens, the local commensal microbial community and environmental antigens. This review will focus on the immune network safeguarding gingival integrity, which is far less understood than that resident at other barrier sites. A detailed understanding of the gingiva-resident immune network is vital as it is the site of the inflammatory disease periodontitis, the most common chronic inflammatory condition in humans which has well-known detrimental systemic effects. Furthering our understanding of how the immune populations within the gingiva develop, are tailored in health, and how this is dysregulated in disease would further the development of effective therapies for periodontitis.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"17 5","pages":"Pages 1141-1150"},"PeriodicalIF":7.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141748610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.mucimm.2024.07.007
Susan B. Morris , Ramon Ocadiz-Ruiz , Nobuhiro Asai , Carrie-Anne Malinczak , Andrew J Rasky , Grace K. Lombardo , Evan M. Velarde , Catherine Ptaschinski , Rachel L Zemans , Nicholas W. Lukacs , Wendy Fonseca
Early-life (EL) respiratory infections increase pulmonary disease risk, especially EL-Respiratory Syncytial Virus (EL-RSV) infections linked to asthma. Mechanisms underlying asthma predisposition remain unknown. In this study, we examined the long-term effects on the lung after four weeks post EL-RSV infection. We identified alterations in the lung epithelial cell, with a rise in the percentage of alveolar type 2 epithelial cells (AT2) and a decreased percentage of cells in the AT1 and AT2-AT1 subclusters, as well as upregulation of Bmp2 and Krt8 genes that are associated with AT2-AT1 trans-differentiation, suggesting potential defects in lung repair processes. We identified persistent upregulation of asthma-associated genes, including Il33. EL-RSV-infected mice allergen-challenged exhibited exacerbated allergic response, with significant upregulation of Il33 in the lung and AT2 cells. Similar long-term effects were observed in mice exposed to EL-IL-1β. Notably, treatment with IL-1ra during acute EL-RSV infection mitigated the long-term alveolar alterations and the allergen-exacerbated response. Finally, epigenetic modifications in the promoter of the Il33 gene were detected in AT2 cells harvested from EL-RSV and EL-IL1β groups, suggesting that long-term alteration in the epithelium after RSV infection is dependent on the IL-1β pathway. This study provides insight into the molecular mechanisms of asthma predisposition after RSV infection.
{"title":"Long-term alterations in lung epithelial cells after EL-RSV infection exacerbate allergic responses through IL-1β-induced pathways","authors":"Susan B. Morris , Ramon Ocadiz-Ruiz , Nobuhiro Asai , Carrie-Anne Malinczak , Andrew J Rasky , Grace K. Lombardo , Evan M. Velarde , Catherine Ptaschinski , Rachel L Zemans , Nicholas W. Lukacs , Wendy Fonseca","doi":"10.1016/j.mucimm.2024.07.007","DOIUrl":"10.1016/j.mucimm.2024.07.007","url":null,"abstract":"<div><div>Early-life (EL) respiratory infections increase pulmonary disease risk, especially EL-Respiratory Syncytial Virus (EL-RSV) infections linked to asthma. Mechanisms underlying asthma predisposition remain unknown. In this study, we examined the long-term effects on the lung after four weeks post EL-RSV infection. We identified alterations in the lung epithelial cell, with a rise in the percentage of alveolar type 2 epithelial cells (AT2) and a decreased percentage of cells in the AT1 and AT2-AT1 subclusters, as well as upregulation of <em>Bmp2</em> and <em>Krt8</em> genes that are associated with AT2-AT1 <em>trans</em>-differentiation, suggesting potential defects in lung repair processes. We identified persistent upregulation of asthma-associated genes, including <em>Il33</em>. EL-RSV-infected mice allergen-challenged exhibited exacerbated allergic response, with significant upregulation of <em>Il33</em> in the lung and AT2 cells. Similar long-term effects were observed in mice exposed to EL-IL-1β. Notably, treatment with IL-1ra during acute EL-RSV infection mitigated the long-term alveolar alterations and the allergen-exacerbated response. Finally, epigenetic modifications in the promoter of the <em>Il33</em> gene were detected in AT2 cells harvested from EL-RSV and EL-IL1β groups, suggesting that long-term alteration in the epithelium after RSV infection is dependent on the IL-1β pathway. This study provides insight into the molecular mechanisms of asthma predisposition after RSV infection.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"17 5","pages":"Pages 1072-1088"},"PeriodicalIF":7.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141788701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.mucimm.2024.05.005
Upon infection, CD8+ T cells that have been primed in the draining lymph nodes migrate to the invaded tissue, where they receive cues prompting their differentiation into tissue-resident memory cells (Trm), which display niche-specific transcriptional features. Despite the importance of these cells, our understanding of their molecular landscape and the signals that dictate their development remains limited, particularly in specific anatomical niches such as the large intestine (LI). Here, we report that LI Trm-generated following oral infection exhibits a distinct transcriptional profile compared to Trm in other tissues. Notably, we observe that local cues play a crucial role in the preferential establishment of LI Trm, favoring precursors that migrate to the tissue early during infection. Our investigations identify cognate antigen recognition as a major driver of Trm differentiation at this anatomical site. Local antigen presentation not only promotes the proliferation of effector cells and memory precursors but also facilitates the acquisition of transcriptional features characteristic of gut Trm. Thus, antigen recognition in the LI favors the establishment of Trm by impacting T cell expansion and gene expression.
感染后,在引流淋巴结中被激活的 CD8+ T 细胞会迁移到受侵袭的组织,在那里它们会接收到促使它们分化为组织驻留记忆细胞(Trm)的信号,这些细胞会显示出龛位特异性转录特征。尽管这些细胞非常重要,但我们对其分子图谱和决定其发育的信号的了解仍然有限,尤其是在大肠(LI)等特定解剖龛位中。在这里,我们报告了口腔感染后产生的大肠Trm与其他组织中的Trm相比表现出不同的转录特征。值得注意的是,我们观察到局部线索在 LI Trm 的优先建立中起着至关重要的作用,有利于感染期间早期迁移到该组织的前体。我们的研究发现,同源抗原识别是这一解剖部位Trm分化的主要驱动力。局部抗原呈递不仅能促进效应细胞和记忆前体的增殖,还能促进获得肠道Trm特有的转录特征。因此,LI 中的抗原识别会影响 T 细胞的扩增和基因表达,从而有利于 Trm 的建立。
{"title":"Local antigen encounter promotes generation of tissue-resident memory T cells in the large intestine","authors":"","doi":"10.1016/j.mucimm.2024.05.005","DOIUrl":"10.1016/j.mucimm.2024.05.005","url":null,"abstract":"<div><div>Upon infection, CD8<sup>+</sup> T cells that have been primed in the draining lymph nodes migrate to the invaded tissue, where they receive cues prompting their differentiation into tissue-resident memory cells (Trm), which display niche-specific transcriptional features. Despite the importance of these cells, our understanding of their molecular landscape and the signals that dictate their development remains limited, particularly in specific anatomical niches such as the large intestine (LI). Here, we report that LI Trm-generated following oral infection exhibits a distinct transcriptional profile compared to Trm in other tissues. Notably, we observe that local cues play a crucial role in the preferential establishment of LI Trm, favoring precursors that migrate to the tissue early during infection. Our investigations identify cognate antigen recognition as a major driver of Trm differentiation at this anatomical site. Local antigen presentation not only promotes the proliferation of effector cells and memory precursors but also facilitates the acquisition of transcriptional features characteristic of gut Trm. Thus, antigen recognition in the LI favors the establishment of Trm by impacting T cell expansion and gene expression.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"17 5","pages":"Pages 810-824"},"PeriodicalIF":7.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141088085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}