Pub Date : 2024-10-01DOI: 10.1016/j.mucimm.2024.06.010
Streptococcus pneumoniae colonization in the upper respiratory tract is linked to pneumococcal disease development, predominantly affecting young children and older adults. As the global population ages and comorbidities increase, there is a heightened concern about this infection. We investigated the immunological responses of older adults to pneumococcal-controlled human infection by analyzing the cellular composition and gene expression in the nasal mucosa. Our comparative analysis with data from a concurrent study in younger adults revealed distinct gene expression patterns in older individuals susceptible to colonization, highlighted by neutrophil activation and elevated levels of CXCL9 and CXCL10. Unlike younger adults challenged with pneumococcus, older adults did not show recruitment of monocytes into the nasal mucosa following nasal colonization. However, older adults who were protected from colonization showed increased degranulation of cluster of differentiation 8+ T cells, both before and after pneumococcal challenge. These findings suggest age-associated cellular changes, in particular enhanced mucosal inflammation, that may predispose older adults to pneumococcal colonization.
肺炎链球菌在上呼吸道的定植与肺炎球菌疾病的发生有关,主要影响幼儿和老年人。随着全球人口的老龄化和并发症的增加,人们对这种感染的关注度也越来越高。我们通过分析鼻粘膜的细胞组成和基因表达,研究了老年人对肺炎球菌控制的人类感染的免疫反应。我们与同时在年轻人中进行的一项研究的数据进行了比较分析,结果发现,易受定植感染的老年人有不同的基因表达模式,其中突出的是中性粒细胞活化以及 CXCL9 和 CXCL10 水平的升高。与受到肺炎球菌挑战的年轻人不同,老年人在鼻腔定植肺炎球菌后并没有表现出单核细胞被招募到鼻粘膜中。然而,受到定植保护的老年人在肺炎球菌挑战前后都表现出 CD8+ T 细胞脱颗粒增加。这些研究结果表明,与年龄相关的细胞变化,尤其是粘膜炎症的增强,可能会使老年人更容易感染肺炎球菌。
{"title":"Inflammation of the nasal mucosa is associated with susceptibility to experimental pneumococcal challenge in older adults","authors":"","doi":"10.1016/j.mucimm.2024.06.010","DOIUrl":"10.1016/j.mucimm.2024.06.010","url":null,"abstract":"<div><div><em>Streptococcus pneumoniae</em> colonization in the upper respiratory tract is linked to pneumococcal disease development, predominantly affecting young children and older adults. As the global population ages and comorbidities increase, there is a heightened concern about this infection. We investigated the immunological responses of older adults to pneumococcal-controlled human infection by analyzing the cellular composition and gene expression in the nasal mucosa. Our comparative analysis with data from a concurrent study in younger adults revealed distinct gene expression patterns in older individuals susceptible to colonization, highlighted by neutrophil activation and elevated levels of CXCL9 and CXCL10. Unlike younger adults challenged with pneumococcus, older adults did not show recruitment of monocytes into the nasal mucosa following nasal colonization. However, older adults who were protected from colonization showed increased degranulation of cluster of differentiation 8+ T cells, both before and after pneumococcal challenge. These findings suggest age-associated cellular changes, in particular enhanced mucosal inflammation, that may predispose older adults to pneumococcal colonization.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"17 5","pages":"Pages 973-989"},"PeriodicalIF":7.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11464406/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141476988","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.2024.07.003
Gila Idelman , Christian F. Rizza , Sahiti Marella , Ankit Sharma , Somdutta Chakraborty , Hock L. Tay , Sunil Tomar , Varsha Ganesan , Charles F. Schuler IV , James R. Baker , Simon P. Hogan
<div><div>Mast cells (MCs) are derived from CD34<sup>+</sup> hematopoietic progenitors, consist of different subtypes, and are involved in several inflammatory conditions. However, our understanding of human MC developmental trajectories and subtypes has been limited by a scarcity of suitable cellular model systems. Herein, we developed an <em>in vitro</em> model of human MC differentiation from induced pluripotent stem cells (iPSC) to study human MC differentiation trajectories. Flow cytometry characterization of hemopoietic cells derived from the myeloid cells-forming complex (MCFC) revealed an initial increase in Lin<sup>-</sup> CD34<sup>+</sup> hematopoietic progenitors within Weeks 1–3, followed by an increase in CD34<sup>-</sup> CD45RA<sup>-</sup> SSC<sup>l</sup><sup>ow</sup> and SSC<sup>high</sup> hematopoietic cells. The Lin<sup>-</sup> CD34<sup>+</sup> hematopoietic progenitors consisted of SSC<sup>low</sup> CD45RA<sup>-</sup> CD123<sup>±</sup> c-Kit<sup>+</sup> FcεRI<sup>+</sup> populations that were β7-integrin<sup>high</sup> CD203c<sup>+</sup> and β7-integrin<sup>high</sup> CD203c<sup>-</sup> cells consistent with CMP<sup>Fc</sup><sup>ε</sup><sup>RI+</sup> cells. Flow cytometry and cytologic analyses of the CD34<sup>-</sup> Lin<sup>-</sup> (SSC<sup>low</sup>) population revealed hypogranular cell populations, predominantly characterized by CD45RA<sup>-</sup> CD123<sup>±</sup> c-Kit<sup>+</sup> FcεRI<sup>-</sup> β7-integrin<sup>low</sup> and CD45RA<sup>-</sup> CD123<sup>±</sup> c-Kit<sup>-</sup> FcεRI<sup>+</sup> β7-integrin<sup>Mid</sup> cells. Analyses of hypergranular SSC<sup>high</sup> cells identified Lin<sup>-</sup> CD34<sup>-</sup> CD45RA<sup>-</sup> c-Kit<sup>+</sup> FcεRI<sup>-</sup> and Lin<sup>-</sup> CD34<sup>-</sup> CD45RA<sup>-</sup> c-Kit<sup>+</sup> FcεRI<sup>+</sup> cells. scRNA-seq analysis of the cells harvested at week 4 of the MCFC culture revealed the presence of monocyte and granulocyte progenitors (n = 547 cells, 26.7 %), Erythrocyte / unknown (n = 85, 4.1 %), neutrophils / myelocytes (n = 211 cells, 10.2 %), mast cell progenitor 1 (n = 599, 29.1 %), mast cell progenitor 2 (n = 152, 7.4 %), committed mast cell precursor (n = 113, 5.5 %), and MCs (n = 353, 17.1 %). In silico analyses of the MC precursor and mature MC populations revealed transcriptionally distinct MC precursor subtype and mature MC states (CMA1<sup>+</sup> and CMA1<sup>-</sup> subtypes). Culturing MC precursor populations in MC maturation media (mast cell media II) led to homogenous mature MC populations as evidenced by high expression of high-affinity IgE receptor, metachromatic granules, presence of MC granule proteins (Tryptase and Chymase) and activation following substance P stimulation and FcεRI crosslinking. This human iPSC-based approach generates MC precursors and phenotypically mature and functional MC populations. This system will be a useful model to generate human MC populations and broaden our understanding of MC biology and transcr
肥大细胞(MC)来源于 CD34+ 造血祖细胞,由不同的亚型组成,参与多种炎症的治疗。然而,由于缺乏合适的细胞模型系统,我们对人类 MC 发育轨迹和亚型的了解受到了限制。在此,我们利用诱导多能干细胞(iPSC)建立了人类 MC 分化的体外模型,以研究人类 MC 的分化轨迹。流式细胞术鉴定了来自髓系细胞形成复合体(MCFC)的造血细胞,发现在第1-3周,Lin- CD34+造血祖细胞开始增加,随后CD34- CD45RA- SSCLow和SSChigh造血细胞增加。Lin- CD34+ 造血祖细胞由 SSClow CD45RA- CD123± c-Kit+ FcERI+ 群体组成,该群体为 β7-integrinhigh CD203c+ 和 β7-integrinhigh CD203c- 细胞,与 CMPFceRI+ 细胞一致。对CD34- Lin-(SSClow)群体的流式细胞术和细胞学分析显示了低颗粒细胞群,主要特征是CD45RA- CD123± c-Kit+ FcERI- β7-integrin-low和CD45RA- CD123± c-Kit- FcERI+ β7-integrin-Mid细胞。对超粒 SSChigh 细胞的分析发现了 Lin- CD34- CD45RA- c-Kit+ FceRI- 和 Lin- CD34- CD45RA- c-Kit+ FceRI+ 细胞。对 MCFC 培养第 4 周收获的细胞进行的 scRNA seq 分析显示存在单核细胞和粒细胞祖细胞(n = 547 个细胞,26.7 %)、红细胞/未知细胞(n = 85,4.1 %)、中性粒细胞/骨髓细胞(n = 211,10.2 %)、肥大细胞祖细胞 1(n = 599,29.1 %)、肥大细胞祖细胞 2(n = 152,7.4 %)、肥大细胞前体(n = 113,5.5 %)和肥大细胞(n = 353,17.1 %)。对肥大细胞前体和成熟肥大细胞群进行的硅学分析表明,肥大细胞前体亚型和成熟肥大细胞状态(CMA1+ 和 CMA1-亚型)在转录上截然不同。在 MC 成熟培养基(肥大细胞培养基 II)中培养 MC 前体群体可产生同质的成熟 MC 群体,表现为高亲和力 IgE 受体的高表达、变色颗粒、MC 颗粒蛋白(胰蛋白酶和糜蛋白酶)的存在以及物质 P 刺激和 FceRI 交联后的活化。这种基于人类 iPSC 的方法可产生 MC 前体和表型成熟的功能性 MC 群体。该系统将成为产生人类 MC 群体的有用模型,并拓宽我们对 MC 生物学和 MC 分化轨迹转录调控的理解。
{"title":"Inducible pluripotent stem cells to study human mast cell trajectories","authors":"Gila Idelman , Christian F. Rizza , Sahiti Marella , Ankit Sharma , Somdutta Chakraborty , Hock L. Tay , Sunil Tomar , Varsha Ganesan , Charles F. Schuler IV , James R. Baker , Simon P. Hogan","doi":"10.1016/j.mucimm.2024.07.003","DOIUrl":"10.1016/j.mucimm.2024.07.003","url":null,"abstract":"<div><div>Mast cells (MCs) are derived from CD34<sup>+</sup> hematopoietic progenitors, consist of different subtypes, and are involved in several inflammatory conditions. However, our understanding of human MC developmental trajectories and subtypes has been limited by a scarcity of suitable cellular model systems. Herein, we developed an <em>in vitro</em> model of human MC differentiation from induced pluripotent stem cells (iPSC) to study human MC differentiation trajectories. Flow cytometry characterization of hemopoietic cells derived from the myeloid cells-forming complex (MCFC) revealed an initial increase in Lin<sup>-</sup> CD34<sup>+</sup> hematopoietic progenitors within Weeks 1–3, followed by an increase in CD34<sup>-</sup> CD45RA<sup>-</sup> SSC<sup>l</sup><sup>ow</sup> and SSC<sup>high</sup> hematopoietic cells. The Lin<sup>-</sup> CD34<sup>+</sup> hematopoietic progenitors consisted of SSC<sup>low</sup> CD45RA<sup>-</sup> CD123<sup>±</sup> c-Kit<sup>+</sup> FcεRI<sup>+</sup> populations that were β7-integrin<sup>high</sup> CD203c<sup>+</sup> and β7-integrin<sup>high</sup> CD203c<sup>-</sup> cells consistent with CMP<sup>Fc</sup><sup>ε</sup><sup>RI+</sup> cells. Flow cytometry and cytologic analyses of the CD34<sup>-</sup> Lin<sup>-</sup> (SSC<sup>low</sup>) population revealed hypogranular cell populations, predominantly characterized by CD45RA<sup>-</sup> CD123<sup>±</sup> c-Kit<sup>+</sup> FcεRI<sup>-</sup> β7-integrin<sup>low</sup> and CD45RA<sup>-</sup> CD123<sup>±</sup> c-Kit<sup>-</sup> FcεRI<sup>+</sup> β7-integrin<sup>Mid</sup> cells. Analyses of hypergranular SSC<sup>high</sup> cells identified Lin<sup>-</sup> CD34<sup>-</sup> CD45RA<sup>-</sup> c-Kit<sup>+</sup> FcεRI<sup>-</sup> and Lin<sup>-</sup> CD34<sup>-</sup> CD45RA<sup>-</sup> c-Kit<sup>+</sup> FcεRI<sup>+</sup> cells. scRNA-seq analysis of the cells harvested at week 4 of the MCFC culture revealed the presence of monocyte and granulocyte progenitors (n = 547 cells, 26.7 %), Erythrocyte / unknown (n = 85, 4.1 %), neutrophils / myelocytes (n = 211 cells, 10.2 %), mast cell progenitor 1 (n = 599, 29.1 %), mast cell progenitor 2 (n = 152, 7.4 %), committed mast cell precursor (n = 113, 5.5 %), and MCs (n = 353, 17.1 %). In silico analyses of the MC precursor and mature MC populations revealed transcriptionally distinct MC precursor subtype and mature MC states (CMA1<sup>+</sup> and CMA1<sup>-</sup> subtypes). Culturing MC precursor populations in MC maturation media (mast cell media II) led to homogenous mature MC populations as evidenced by high expression of high-affinity IgE receptor, metachromatic granules, presence of MC granule proteins (Tryptase and Chymase) and activation following substance P stimulation and FcεRI crosslinking. This human iPSC-based approach generates MC precursors and phenotypically mature and functional MC populations. This system will be a useful model to generate human MC populations and broaden our understanding of MC biology and transcr","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"17 5","pages":"Pages 1029-1044"},"PeriodicalIF":7.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141748611","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.2024.07.005
Bingtai Lu , Yanfang Zhang , Jun Wang , Diyuan Yang , Ming Liu , Liuheyi Ma , Weijing Yi , Yufeng Liang , Yingyi Xu , Huifeng Fan , Wei Liu , Jue Tang , Sengqiang Zeng , Li Cai , Li Zhang , Junli Nie , Fen Zhang , Xiaoqiong Gu , Jaime S. Rosa Duque , Gen Lu , Yuxia Zhang
Human adenovirus (HAdV) pneumonia poses a major health burden for young children, however, factors that contribute to disease severity remain elusive. We analyzed immune cells from bronchoalveolar lavage (BAL) of children with HAdV pneumonia and found that CD19+CD21low B cells were significantly enriched in the BAL and were associated with increased autoantibody concentrations and disease severity. Myeloid cells, PD-1+CD4+ T helper cells and CD21low B cells formed tertiary lymphoid structures within the respiratory tracts. Myeloid cells promoted autoantibody production by expressing high amounts of B cell activating factor (BAFF). In contrast, PD-1+CD4+ T helper cells induced production of IgG1 and IgG3 antibodies but suppressed autoreactive IgGs by initiating B cell receptor editing. In summary, this study reveals cellular components involved in protective versus autoreactive immune pathways in the respiratory tract, and these findings provide potential therapeutic targets for severe HAdV lower respiratory tract infections.
人类腺病毒(HAdV)肺炎对幼儿的健康造成了重大负担,然而,导致疾病严重程度的因素仍然难以捉摸。我们分析了患 HAdV 肺炎儿童支气管肺泡灌洗液(BAL)中的免疫细胞,发现 CD19+CD21 低 B 细胞在 BAL 中明显富集,并与自身抗体浓度增加和疾病严重程度相关。髓系细胞、PD-1+CD4+ T 辅助细胞和 CD21low B 细胞在呼吸道内形成三级淋巴结构。髓系细胞通过表达大量的B细胞活化因子(BAFF)来促进自身抗体的产生。相反,PD-1+CD4+ T 辅助细胞诱导产生 IgG1 和 IgG3 抗体,但通过启动 B 细胞受体编辑抑制了自身反应性 IgG。总之,这项研究揭示了呼吸道中参与保护性免疫途径和自反应性免疫途径的细胞成分,这些发现为严重的HAdV下呼吸道感染提供了潜在的治疗靶点。
{"title":"PD1+CD4+ T cells promote receptor editing and suppress autoreactivity of CD19+CD21low B cells within the lower respiratory airways in adenovirus pneumonia","authors":"Bingtai Lu , Yanfang Zhang , Jun Wang , Diyuan Yang , Ming Liu , Liuheyi Ma , Weijing Yi , Yufeng Liang , Yingyi Xu , Huifeng Fan , Wei Liu , Jue Tang , Sengqiang Zeng , Li Cai , Li Zhang , Junli Nie , Fen Zhang , Xiaoqiong Gu , Jaime S. Rosa Duque , Gen Lu , Yuxia Zhang","doi":"10.1016/j.mucimm.2024.07.005","DOIUrl":"10.1016/j.mucimm.2024.07.005","url":null,"abstract":"<div><div>Human adenovirus (HAdV) pneumonia poses a major health burden for young children, however, factors that contribute to disease severity remain elusive. We analyzed immune cells from bronchoalveolar lavage (BAL) of children with HAdV pneumonia and found that CD19<sup>+</sup>CD21<sup>low</sup> B cells were significantly enriched in the BAL and were associated with increased autoantibody concentrations and disease severity. Myeloid cells, PD-1<sup>+</sup>CD4<sup>+</sup> T helper cells and CD21<sup>low</sup> B cells formed tertiary lymphoid structures within the respiratory tracts. Myeloid cells promoted autoantibody production by expressing high amounts of B cell activating factor (BAFF). In contrast, PD-1<sup>+</sup>CD4<sup>+</sup> T helper cells induced production of IgG1 and IgG3 antibodies but suppressed autoreactive IgGs by initiating B cell receptor editing. In summary, this study reveals cellular components involved in protective versus autoreactive immune pathways in the respiratory tract, and these findings provide potential therapeutic targets for severe HAdV lower respiratory tract infections.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"17 5","pages":"Pages 1045-1059"},"PeriodicalIF":7.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141748612","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 : 2024-09-27DOI: 10.1016/j.mucimm.2024.09.006
Taylor M Benson, Gary E Markey, Juliet A Hammer, Luke Simerly, Monika Dzieciatkowska, Kimberly R Jordan, Kelley E Capocelli, Kathleen M Scullion, Louise Crowe, Sinéad Ryan, Jennifer O Black, Taylor Crue, Rachel Andrews, Cassandra Burger, Eóin N McNamee, Glenn T Furuta, Calies Menard-Katcher, Joanne C Masterson
Atopic diseases such as Eosinophilic Esophagitis (EoE) often progress into fibrosis (FS-EoE), compromising organ function with limited targeted treatment options. Mechanistic understanding of FS-EoE progression is confounded by the lack of preclinical models and the heavy focus of research on eosinophils themselves. We found that macrophage accumulation precedes esophageal fibrosis in FS-EoE patients. We developed a FS-EoE model via chronic administration of oxazalone allergen, in a transgenic mouse over-expressing esophageal epithelial hIL-5 (L2-IL5OXA). These mice display striking histopathologic features congruent with that found in FS-EoE patients. Unbiased proteomic analysis, using a unique extracellular-matrix (ECM) focused technique, identified an inflammation-reactive provisional basal lamina membrane signature and this was validated in two independent EoE patient RNA-sequencing/proteomic cohorts, supporting model significance. A wound healing signature was also observed involving hemostasis-associated molecules previously unnoted in EoE. We further identified the ECM glycoprotein, Tenascin-C (TNC), and the stress-responsive keratin-16 (KRT16) as IL-4 and IL-13 responsive mediators, acting as biomarkers of FS-EoE. To mechanistically address how the immune infiltrate shapes FS-EoE progression, we phenotyped the major immune cell subsets that coalesce with fibrosis in both the L2-IL5OXA mice and in FS-EoE patients. We found that macrophage are required for matrisome and cytoskeletal remodeling. Importantly, we show that macrophage accumulation precedes esophageal fibrosis and provide a novel therapeutic target in FS-EoE as their depletion with anti-CSF1 attenuated reactive matrisome and cytoskeletal changes. Thus, macrophage-based treatments and the exploration of TNC and KRT16 as biomarkers may provide novel therapeutic options for patients with fibrostenosis.
{"title":"CSF1-dependent macrophage support matrisome and epithelial stress-induced keratin remodeling in Eosinophilic esophagitis.","authors":"Taylor M Benson, Gary E Markey, Juliet A Hammer, Luke Simerly, Monika Dzieciatkowska, Kimberly R Jordan, Kelley E Capocelli, Kathleen M Scullion, Louise Crowe, Sinéad Ryan, Jennifer O Black, Taylor Crue, Rachel Andrews, Cassandra Burger, Eóin N McNamee, Glenn T Furuta, Calies Menard-Katcher, Joanne C Masterson","doi":"10.1016/j.mucimm.2024.09.006","DOIUrl":"10.1016/j.mucimm.2024.09.006","url":null,"abstract":"<p><p>Atopic diseases such as Eosinophilic Esophagitis (EoE) often progress into fibrosis (FS-EoE), compromising organ function with limited targeted treatment options. Mechanistic understanding of FS-EoE progression is confounded by the lack of preclinical models and the heavy focus of research on eosinophils themselves. We found that macrophage accumulation precedes esophageal fibrosis in FS-EoE patients. We developed a FS-EoE model via chronic administration of oxazalone allergen, in a transgenic mouse over-expressing esophageal epithelial hIL-5 (L2-IL5<sup>OXA</sup>). These mice display striking histopathologic features congruent with that found in FS-EoE patients. Unbiased proteomic analysis, using a unique extracellular-matrix (ECM) focused technique, identified an inflammation-reactive provisional basal lamina membrane signature and this was validated in two independent EoE patient RNA-sequencing/proteomic cohorts, supporting model significance. A wound healing signature was also observed involving hemostasis-associated molecules previously unnoted in EoE. We further identified the ECM glycoprotein, Tenascin-C (TNC), and the stress-responsive keratin-16 (KRT16) as IL-4 and IL-13 responsive mediators, acting as biomarkers of FS-EoE. To mechanistically address how the immune infiltrate shapes FS-EoE progression, we phenotyped the major immune cell subsets that coalesce with fibrosis in both the L2-IL5<sup>OXA</sup> mice and in FS-EoE patients. We found that macrophage are required for matrisome and cytoskeletal remodeling. Importantly, we show that macrophage accumulation precedes esophageal fibrosis and provide a novel therapeutic target in FS-EoE as their depletion with anti-CSF1 attenuated reactive matrisome and cytoskeletal changes. Thus, macrophage-based treatments and the exploration of TNC and KRT16 as biomarkers may provide novel therapeutic options for patients with fibrostenosis.</p>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350419","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 : 2024-09-26DOI: 10.1016/j.mucimm.2024.09.005
Maria-Bernadette Madel, Lidia Ibáñez, Thomas Ciucci, Julia Halper, Antoine Boutin, Ghada Beldi, Alice C Lavanant, Henri-Jean Garchon, Matthieu Rouleau, Christopher G Mueller, Laurent Peyrin-Biroulet, David Moulin, Claudine Blin-Wakkach, Abdelilah Wakkach
Inflammatory bowel disease (IBD) is characterized by very severe intestinal inflammation associated with extra-intestinal manifestations. One of the most critical ones is bone destruction, which remains a major cause of morbidity and a risk factor for osteopenia and osteoporosis in IBD patients. In various mouse models of IBD, we and other have demonstrated concomitant bone loss due to a significant increase in osteoclast activity. Besides bone resorption, osteoclasts are known to control hematopoietic niches in vivo and modulate inflammatory responses in vitro, suggesting they may participate in chronic inflammation in vivo. Here, using different models of colitis, we showed that osteoclast inhibition significantly reduced disease severity and that induction of osteoclast differentiation by RANKL contributed to disease worsening. Our results demonstrate a direct link between osteoclast activity and myeloid cell accumulation in the intestine during colitis. RNAseq analysis of osteoclasts from colitic mice revealed overexpression of genes involved in the remodeling of hematopoietic stem cell niches. We also demonstrated that osteoclasts induced hematopoietic progenitor proliferation accompanied by a myeloid skewing in the early phases of colitis, which was confirmed in a model of RANKL-induced osteoclastogenesis. Mechanistically, inhibition of TNF-α reduced the induction of myeloid skewing by OCL both in vitro and in vivo. Lastly, we observed that osteoclastic activity and the proportion of myeloid cells in the blood are positively correlated in patients with Crohn's disease. Collectively, our results shed light on a new role of osteoclasts in colitis in vivo, demonstrating they exert their colitogenic activity through an early action on hematopoiesis, leading to an increase in myelopoiesis sustaining gut inflammation.
{"title":"Dysregulated myeloid differentiation in colitis is induced by inflammatory osteoclasts in a TNFα-dependent manner.","authors":"Maria-Bernadette Madel, Lidia Ibáñez, Thomas Ciucci, Julia Halper, Antoine Boutin, Ghada Beldi, Alice C Lavanant, Henri-Jean Garchon, Matthieu Rouleau, Christopher G Mueller, Laurent Peyrin-Biroulet, David Moulin, Claudine Blin-Wakkach, Abdelilah Wakkach","doi":"10.1016/j.mucimm.2024.09.005","DOIUrl":"10.1016/j.mucimm.2024.09.005","url":null,"abstract":"<p><p>Inflammatory bowel disease (IBD) is characterized by very severe intestinal inflammation associated with extra-intestinal manifestations. One of the most critical ones is bone destruction, which remains a major cause of morbidity and a risk factor for osteopenia and osteoporosis in IBD patients. In various mouse models of IBD, we and other have demonstrated concomitant bone loss due to a significant increase in osteoclast activity. Besides bone resorption, osteoclasts are known to control hematopoietic niches in vivo and modulate inflammatory responses in vitro, suggesting they may participate in chronic inflammation in vivo. Here, using different models of colitis, we showed that osteoclast inhibition significantly reduced disease severity and that induction of osteoclast differentiation by RANKL contributed to disease worsening. Our results demonstrate a direct link between osteoclast activity and myeloid cell accumulation in the intestine during colitis. RNAseq analysis of osteoclasts from colitic mice revealed overexpression of genes involved in the remodeling of hematopoietic stem cell niches. We also demonstrated that osteoclasts induced hematopoietic progenitor proliferation accompanied by a myeloid skewing in the early phases of colitis, which was confirmed in a model of RANKL-induced osteoclastogenesis. Mechanistically, inhibition of TNF-α reduced the induction of myeloid skewing by OCL both in vitro and in vivo. Lastly, we observed that osteoclastic activity and the proportion of myeloid cells in the blood are positively correlated in patients with Crohn's disease. Collectively, our results shed light on a new role of osteoclasts in colitis in vivo, demonstrating they exert their colitogenic activity through an early action on hematopoiesis, leading to an increase in myelopoiesis sustaining gut inflammation.</p>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350420","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 : 2024-09-26DOI: 10.1016/j.mucimm.2024.09.004
Maud Heredia, Mohammed Charrout, Renz C W Klomberg, Martine A Aardoom, Maria M E Jongsma, Polychronis Kemos, Danielle H Hulleman-van Haaften, Bastiaan Tuk, Lisette A van Berkel, Brenda Bley Folly, Beatriz Calado, Sandrine Nugteren, Ytje Simons-Oosterhuis, Michail Doukas, Mathijs A Sanders, Gregory van Beek, Frank M Ruemmele, Nicholas M Croft, Ahmed Mahfouz, Marcel J T Reinders, Johanna C Escher, Lissy de Ridder, Janneke N Samsom
Inflammatory bowel disease (IBD) chronicity results from memory T helper cell (Tmem) reactivation. Identifying patient-specific immunotypes is crucial for tailored treatment. We conducted a comprehensive study integrating circulating immune proteins and circulating Tmem, with intestinal tissue histology and mRNA analysis, in therapy-naïve pediatric IBD (Crohn's disease, CD: n = 62; ulcerative colitis, UC: n = 20; age-matched controls n = 43), and after 10-12 weeks' induction therapy. At diagnosis, plasma protein profiles unveiled two UC and three CD clusters with distinct disease courses. UC patients displayed unchanged circulating Tmem, while CD exhibited increased frequencies of gut-homing ex-Th17, known for high IFN-γ production. UC#2 had elevated Th17/neutrophil-pathway-related proteins and severe disease, with higher endoscopic and histological damage and Th17/neutrophil infiltration. Although both UC#1 and UC#2 responded to therapy, UC#2 required earlier immunomodulation. CD#3 had lower plasma protein concentrations, especially IFN-γ pathway proteins, fewer gut-homing ex-Th17 and clinically milder disease, confirmed by intestinal gene expression. CD#1 and CD#2 had comparably high Th1-related immune profiles, but CD#1 exhibited higher concentrations of proteins previously associated with poorer prognosis. Both CD clusters responded to induction therapy, with similar one-year outcomes. This study highlights feasibility of discriminating patient-specific immunotypes in IBD, advancing our understanding of immune pathogenesis, needed for tailored treatment strategies.
{"title":"Combined plasma protein and memory T cell profiling discern IBD-patient-immunotypes related to intestinal disease and treatment outcomes.","authors":"Maud Heredia, Mohammed Charrout, Renz C W Klomberg, Martine A Aardoom, Maria M E Jongsma, Polychronis Kemos, Danielle H Hulleman-van Haaften, Bastiaan Tuk, Lisette A van Berkel, Brenda Bley Folly, Beatriz Calado, Sandrine Nugteren, Ytje Simons-Oosterhuis, Michail Doukas, Mathijs A Sanders, Gregory van Beek, Frank M Ruemmele, Nicholas M Croft, Ahmed Mahfouz, Marcel J T Reinders, Johanna C Escher, Lissy de Ridder, Janneke N Samsom","doi":"10.1016/j.mucimm.2024.09.004","DOIUrl":"10.1016/j.mucimm.2024.09.004","url":null,"abstract":"<p><p>Inflammatory bowel disease (IBD) chronicity results from memory T helper cell (Tmem) reactivation. Identifying patient-specific immunotypes is crucial for tailored treatment. We conducted a comprehensive study integrating circulating immune proteins and circulating Tmem, with intestinal tissue histology and mRNA analysis, in therapy-naïve pediatric IBD (Crohn's disease, CD: n = 62; ulcerative colitis, UC: n = 20; age-matched controls n = 43), and after 10-12 weeks' induction therapy. At diagnosis, plasma protein profiles unveiled two UC and three CD clusters with distinct disease courses. UC patients displayed unchanged circulating Tmem, while CD exhibited increased frequencies of gut-homing ex-Th17, known for high IFN-γ production. UC#2 had elevated Th17/neutrophil-pathway-related proteins and severe disease, with higher endoscopic and histological damage and Th17/neutrophil infiltration. Although both UC#1 and UC#2 responded to therapy, UC#2 required earlier immunomodulation. CD#3 had lower plasma protein concentrations, especially IFN-γ pathway proteins, fewer gut-homing ex-Th17 and clinically milder disease, confirmed by intestinal gene expression. CD#1 and CD#2 had comparably high Th1-related immune profiles, but CD#1 exhibited higher concentrations of proteins previously associated with poorer prognosis. Both CD clusters responded to induction therapy, with similar one-year outcomes. This study highlights feasibility of discriminating patient-specific immunotypes in IBD, advancing our understanding of immune pathogenesis, needed for tailored treatment strategies.</p>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350418","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 : 2024-09-16DOI: 10.1016/j.mucimm.2024.09.003
Maik Luu,Felix F Krause,Heide Monning,Anne Wempe,Hanna Leister,Lisa Mainieri,Sarah Staudt,Kai Ziegler-Martin,Kira Mangold,Nora Kappelhoff,Yoav D Shaul,Stephan Göttig,Carlos Plaza-Sirvent,Leon N Schulte,Isabelle Bekeredjian-Ding,Ingo Schmitz,Ulrich Steinhoff,Alexander Visekruna
The host-microbiome axis has been implicated in promoting anti-inflammatory immune responses. Yet, the underlying molecular mechanisms of commensal-mediated IL-10 production by regulatory B cells (Bregs) are not fully elucidated. Here, we demonstrate that bacterial CpG motifs trigger the signaling downstream of TLR9 promoting IκBNS-mediated expression of Blimp-1, a transcription regulator of IL-10. Surprisingly, this effect was counteracted by the NF-κB transcription factor c-Rel. A functional screen for intestinal bacterial species identified the commensal Clostridium sporogenes, secreting high amounts of short-chain fatty acids (SCFAs) and branched-chain fatty acids (BCFAs), as an amplifier of IL-10 production by promoting sustained mTOR signaling in B cells. Consequently, enhanced Breg functionality was achieved by combining CpG with the SCFA butyrate or the BCFA isovalerate thereby synergizing TLR- and mTOR-mediated pathways. Collectively, Bregs required two bacterial signals (butyrate and CpG) to elicit their full suppressive capacity and ameliorate T cell-mediated intestinal inflammation. Our study has dissected the molecular pathways induced by bacterial factors, which might contribute not only to better understanding of host-microbiome interactions, but also to exploration of new strategies for improvement of anti-inflammatory cellular therapy.
{"title":"Dissecting the metabolic signaling pathways by which microbial molecules drive the differentiation of regulatory B cells.","authors":"Maik Luu,Felix F Krause,Heide Monning,Anne Wempe,Hanna Leister,Lisa Mainieri,Sarah Staudt,Kai Ziegler-Martin,Kira Mangold,Nora Kappelhoff,Yoav D Shaul,Stephan Göttig,Carlos Plaza-Sirvent,Leon N Schulte,Isabelle Bekeredjian-Ding,Ingo Schmitz,Ulrich Steinhoff,Alexander Visekruna","doi":"10.1016/j.mucimm.2024.09.003","DOIUrl":"https://doi.org/10.1016/j.mucimm.2024.09.003","url":null,"abstract":"The host-microbiome axis has been implicated in promoting anti-inflammatory immune responses. Yet, the underlying molecular mechanisms of commensal-mediated IL-10 production by regulatory B cells (Bregs) are not fully elucidated. Here, we demonstrate that bacterial CpG motifs trigger the signaling downstream of TLR9 promoting IκBNS-mediated expression of Blimp-1, a transcription regulator of IL-10. Surprisingly, this effect was counteracted by the NF-κB transcription factor c-Rel. A functional screen for intestinal bacterial species identified the commensal Clostridium sporogenes, secreting high amounts of short-chain fatty acids (SCFAs) and branched-chain fatty acids (BCFAs), as an amplifier of IL-10 production by promoting sustained mTOR signaling in B cells. Consequently, enhanced Breg functionality was achieved by combining CpG with the SCFA butyrate or the BCFA isovalerate thereby synergizing TLR- and mTOR-mediated pathways. Collectively, Bregs required two bacterial signals (butyrate and CpG) to elicit their full suppressive capacity and ameliorate T cell-mediated intestinal inflammation. Our study has dissected the molecular pathways induced by bacterial factors, which might contribute not only to better understanding of host-microbiome interactions, but also to exploration of new strategies for improvement of anti-inflammatory cellular therapy.","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"10 1","pages":""},"PeriodicalIF":8.0,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142254726","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}
Dietary micronutrients, particularly vitamin B12 (VB12), profoundly influence the physiological maintenance and function of intestinal cells. However, it is still unclear whether VB12 modulates the transcriptional and metabolic programming of ileal macrophages (iMacs), thereby contributing to intestinal homeostasis. Using multiomic approaches, we demonstrated that VB12 primarily supports the cell cycle activity and mitochondrial metabolism of iMacs, resulting in increased cell frequency compared to VB12 deficiency. VB12 also retained the ability to promote maintenance and metabolic regulation of iMacs during intestinal infection with Typhimurium (STm). On the contrary, depletion of iMacs by inhibiting CSF1R signaling significantly increased host susceptibility to STm and prevented VB12-mediated pathogen reduction. These results thus suggest that regulation of VB12-dependent iMacs critically controls STm expansion, which may be of new relevance to advance our understanding of this vitamin and to strategically formulate sustainable therapeutic nutritional regimens that improve human gut health.
{"title":"Controlling functional homeostasis of ileal resident macrophages by vitamin B12 during steady state and Salmonella infection in mice","authors":"Yong Ge, Mojgan Zadeh, Cheshta Sharma, Yang-Ding Lin, Alexey A. Soshnev, Mansour Mohamadzadeh","doi":"10.1016/j.mucimm.2024.08.011","DOIUrl":"https://doi.org/10.1016/j.mucimm.2024.08.011","url":null,"abstract":"Dietary micronutrients, particularly vitamin B12 (VB12), profoundly influence the physiological maintenance and function of intestinal cells. However, it is still unclear whether VB12 modulates the transcriptional and metabolic programming of ileal macrophages (iMacs), thereby contributing to intestinal homeostasis. Using multiomic approaches, we demonstrated that VB12 primarily supports the cell cycle activity and mitochondrial metabolism of iMacs, resulting in increased cell frequency compared to VB12 deficiency. VB12 also retained the ability to promote maintenance and metabolic regulation of iMacs during intestinal infection with Typhimurium (STm). On the contrary, depletion of iMacs by inhibiting CSF1R signaling significantly increased host susceptibility to STm and prevented VB12-mediated pathogen reduction. These results thus suggest that regulation of VB12-dependent iMacs critically controls STm expansion, which may be of new relevance to advance our understanding of this vitamin and to strategically formulate sustainable therapeutic nutritional regimens that improve human gut health.","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"65 1","pages":""},"PeriodicalIF":8.0,"publicationDate":"2024-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142183290","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 : 2024-09-07DOI: 10.1016/j.mucimm.2024.08.012
Julie Drieu La Rochelle, Josie Ward, Emily Stenke, Yuting Yin, Misaki Matsumoto, Richard Jennings, Gabriella Aviello, Ulla G Knaus
Inflammation of the ileum, or ileitis, is commonly caused by Crohn's disease (CD) but can also accompany ulcerative colitis (backwash ileitis), infections or drug-related damage. Oxidative tissue injury triggered by reactive oxygen species (ROS) is considered part of the ileitis etiology. However, not only elevated ROS but also permanently decreased ROS are associated with inflammatory bowel disease (IBD). While very early onset IBD (VEO-IBD) is associated with a spectrum of NOX1 variants, how NOX1 inactivation contributes to disease development remains ill-defined. Besides propagating signaling responses, NOX1 provides superoxide for peroxynitrite formation in the epithelial barrier. Here we report that NOX4, an H2O2-generating NADPH oxidase with documented tissue protective effects in the intestine and other tissues, limits the generation of ileal peroxynitrite by NOX1/NOS2. Deletion of NOX4 leads to persistent peroxynitrite excess, hyperpermeability, villus blunting, muscular hypertrophy, chemokine/cytokine upregulation and dysbiosis. Conversely, SAMP1/YitFc mice, a CD-like ileitis model, showed age-dependent NOX1/NOS2 downregulation preventing ileal peroxynitrite formation in homeostasis and LPS-induced acute inflammation. Deficiency in NOX1 correlated with the upregulation of antimicrobial peptides, suggesting that ileal peroxynitrite acts as chemical barrier and microbiota modifier in the ileum.
{"title":"Dysregulated NOX1-NOS2 activity as hallmark of ileitis in mice.","authors":"Julie Drieu La Rochelle, Josie Ward, Emily Stenke, Yuting Yin, Misaki Matsumoto, Richard Jennings, Gabriella Aviello, Ulla G Knaus","doi":"10.1016/j.mucimm.2024.08.012","DOIUrl":"10.1016/j.mucimm.2024.08.012","url":null,"abstract":"<p><p>Inflammation of the ileum, or ileitis, is commonly caused by Crohn's disease (CD) but can also accompany ulcerative colitis (backwash ileitis), infections or drug-related damage. Oxidative tissue injury triggered by reactive oxygen species (ROS) is considered part of the ileitis etiology. However, not only elevated ROS but also permanently decreased ROS are associated with inflammatory bowel disease (IBD). While very early onset IBD (VEO-IBD) is associated with a spectrum of NOX1 variants, how NOX1 inactivation contributes to disease development remains ill-defined. Besides propagating signaling responses, NOX1 provides superoxide for peroxynitrite formation in the epithelial barrier. Here we report that NOX4, an H<sub>2</sub>O<sub>2</sub>-generating NADPH oxidase with documented tissue protective effects in the intestine and other tissues, limits the generation of ileal peroxynitrite by NOX1/NOS2. Deletion of NOX4 leads to persistent peroxynitrite excess, hyperpermeability, villus blunting, muscular hypertrophy, chemokine/cytokine upregulation and dysbiosis. Conversely, SAMP1/YitFc mice, a CD-like ileitis model, showed age-dependent NOX1/NOS2 downregulation preventing ileal peroxynitrite formation in homeostasis and LPS-induced acute inflammation. Deficiency in NOX1 correlated with the upregulation of antimicrobial peptides, suggesting that ileal peroxynitrite acts as chemical barrier and microbiota modifier in the ileum.</p>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142154590","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}
Postoperative cognitive dysfunction (POCD) is a prevalent neurological complication that can impair learning and memory for days, months, or even years after anesthesia/surgery. POCD is strongly associated with an altered composition of the gut microbiota (dysbiosis), but the accompanying metabolic changes and their role in gut-brain communication and POCD pathogenesis remain unclear. Here, the present study reports that anesthesia/surgery in aged mice induces elevated intestinal indoleamine 2,3-dioxygenase (IDO) activity, which shiftes intestinal tryptophan (TRP) metabolism toward more IDO-catalyzed kynurenine (KYN) and less gut bacteria-catabolized indoleacetic acid (IAA). Both anesthesia/surgery and intraperitoneal KYN administration induce increased KYN levels that correlate with impaired spatial learning and memory, whereas dietary IAA supplementation attenuates the anesthesia/surgery-induced cognitive impairment. Mechanistically, anesthesia/surgery increases the proportion of interferon-γ (IFN-γ)-producing group 1 innate lymphoid cells (ILC1) in the small intestine lamina propria and elevates intestinal IDO expression and activity, as indicated by the higher ratio of KYN to TRP. The IDO inhibitor 1-MT and antibodies targeting IFN-γ or ILCs mitigate anesthesia/surgery-induced cognitive dysfunction, suggesting that intestinal ILC1 expansion and the ensuing IFN-γ-induced IDO upregulation may be the primary pathway mediating the shift to the KYN pathway in POCD. The ILC1-KYN pathway in the intestine could be a promising therapeutic target for POCD.
术后认知功能障碍(POCD)是一种常见的神经系统并发症,可在麻醉/手术后数天、数月甚至数年内影响学习和记忆。POCD 与肠道微生物群组成的改变(菌群失调)密切相关,但伴随而来的代谢变化及其在肠脑沟通和 POCD 发病机制中的作用仍不清楚。本研究报告了老年小鼠的麻醉/手术诱导肠道吲哚胺 2,3-二氧化酶(IDO)活性升高,从而使肠道色氨酸(TRP)代谢转向更多的 IDO 催化的犬尿氨酸(KYN)和更少的肠道细菌代谢的吲哚乙酸(IAA)。麻醉/手术和腹腔注射 KYN 都会引起 KYN 水平升高,而 KYN 水平升高与空间学习和记忆受损有关,而膳食中补充 IAA 则会减轻麻醉/手术引起的认知障碍。从机理上讲,麻醉/手术增加了小肠固有层中产生干扰素-γ(IFN-γ)的第1组先天性淋巴细胞(ILC1)的比例,并提高了肠道IDO的表达和活性,KYN与TRP的比例升高就表明了这一点。IDO抑制剂1-MT和针对IFN-γ或ILC的抗体可减轻麻醉/手术诱发的认知功能障碍,这表明肠道ILC1的扩张和随之而来的IFN-γ诱导的IDO上调可能是POCD向KYN途径转变的主要介导途径。肠道中的 ILC1-KYN 通路可能是治疗 POCD 的一个很有前景的靶点。
{"title":"The Kynurenine Pathway Regulated by Intestinal Innate Lymphoid Cells Mediates Postoperative Cognitive Dysfunction.","authors":"Wan-Bing Dai,Xiao Zhang,Xu-Liang Jiang,Yi-Zhe Zhang,Ling-Ke Chen,Wei-Tian Tian,Xiao-Xin Zhou,Xiao-Yu Sun,Li-Li Huang,Xi-Yao Gu,Xue-Mei Chen,Xiao-Dan Wu,Jie Tian,Wei-Feng Yu,Lei Shen,Dian-San Su","doi":"10.1016/j.mucimm.2024.09.002","DOIUrl":"https://doi.org/10.1016/j.mucimm.2024.09.002","url":null,"abstract":"Postoperative cognitive dysfunction (POCD) is a prevalent neurological complication that can impair learning and memory for days, months, or even years after anesthesia/surgery. POCD is strongly associated with an altered composition of the gut microbiota (dysbiosis), but the accompanying metabolic changes and their role in gut-brain communication and POCD pathogenesis remain unclear. Here, the present study reports that anesthesia/surgery in aged mice induces elevated intestinal indoleamine 2,3-dioxygenase (IDO) activity, which shiftes intestinal tryptophan (TRP) metabolism toward more IDO-catalyzed kynurenine (KYN) and less gut bacteria-catabolized indoleacetic acid (IAA). Both anesthesia/surgery and intraperitoneal KYN administration induce increased KYN levels that correlate with impaired spatial learning and memory, whereas dietary IAA supplementation attenuates the anesthesia/surgery-induced cognitive impairment. Mechanistically, anesthesia/surgery increases the proportion of interferon-γ (IFN-γ)-producing group 1 innate lymphoid cells (ILC1) in the small intestine lamina propria and elevates intestinal IDO expression and activity, as indicated by the higher ratio of KYN to TRP. The IDO inhibitor 1-MT and antibodies targeting IFN-γ or ILCs mitigate anesthesia/surgery-induced cognitive dysfunction, suggesting that intestinal ILC1 expansion and the ensuing IFN-γ-induced IDO upregulation may be the primary pathway mediating the shift to the KYN pathway in POCD. The ILC1-KYN pathway in the intestine could be a promising therapeutic target for POCD.","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"11 8 1","pages":""},"PeriodicalIF":8.0,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142183289","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}