Pub Date : 2024-12-01DOI: 10.1016/j.mucimm.2024.08.006
Amanpreet Singh Chawla , Maud Vandereyken , Maykel Arias , Llipsy Santiago , Dina Dikovskaya , Chi Nguyen , Neema Skariah , Nicolas Wenner , Natasha B. Golovchenko , Sarah J. Thomson , Edna Ondari , Marcela Garzón-Tituaña , Christopher J. Anderson , Megan Bergkessel , Jay C. D. Hinton , Karen L. Edelblum , Julian Pardo , Mahima Swamy
Intestinal intraepithelial T lymphocytes (IEL) constitutively express high amounts of the cytotoxic proteases Granzymes (Gzm) A and B and are therefore thought to protect the intestinal epithelium against infection by killing infected epithelial cells. However, the role of IEL granzymes in a protective immune response has yet to be demonstrated. We show that GzmA and GzmB are required to protect mice against oral, but not intravenous, infection with Salmonella enterica serovar Typhimurium, consistent with an intestine-specific role. IEL-intrinsic granzymes mediate the protective effects by controlling intracellular bacterial growth and aiding in cell-intrinsic pyroptotic cell death of epithelial cells. Surprisingly, we found that both granzymes play non-redundant roles. GzmB-/- mice carried significantly lower burdens of Salmonella, as predominant GzmA-mediated cell death effectively reduced bacterial translocation across the intestinal barrier. Conversely, in GzmA-/- mice, GzmB-driven apoptosis favored luminal Salmonella growth by providing nutrients, while still reducing translocation across the epithelial barrier. Together, the concerted actions of both GzmA and GzmB balance cell death mechanisms at the intestinal epithelium to provide optimal control that Salmonella cannot subvert.
{"title":"Distinct cell death pathways induced by granzymes collectively protect against intestinal Salmonella infection","authors":"Amanpreet Singh Chawla , Maud Vandereyken , Maykel Arias , Llipsy Santiago , Dina Dikovskaya , Chi Nguyen , Neema Skariah , Nicolas Wenner , Natasha B. Golovchenko , Sarah J. Thomson , Edna Ondari , Marcela Garzón-Tituaña , Christopher J. Anderson , Megan Bergkessel , Jay C. D. Hinton , Karen L. Edelblum , Julian Pardo , Mahima Swamy","doi":"10.1016/j.mucimm.2024.08.006","DOIUrl":"10.1016/j.mucimm.2024.08.006","url":null,"abstract":"<div><div>Intestinal intraepithelial T lymphocytes (IEL) constitutively express high amounts of the cytotoxic proteases Granzymes (Gzm) A and B and are therefore thought to protect the intestinal epithelium against infection by killing infected epithelial cells. However, the role of IEL granzymes in a protective immune response has yet to be demonstrated. We show that GzmA and GzmB are required to protect mice against oral, but not intravenous, infection with <em>Salmonella enterica</em> serovar Typhimurium<em>,</em> consistent with an intestine-specific role. IEL-intrinsic granzymes mediate the protective effects by controlling intracellular bacterial growth and aiding in cell-intrinsic pyroptotic cell death of epithelial cells. Surprisingly, we found that both granzymes play non-redundant roles. <em>GzmB<sup>-/-</sup></em> mice carried significantly lower burdens of <em>Salmonella</em>, as predominant GzmA-mediated cell death effectively reduced bacterial translocation across the intestinal barrier. Conversely, in <em>GzmA<sup>-/-</sup></em> mice, GzmB-driven apoptosis favored luminal <em>Salmonella</em> growth by providing nutrients, while still reducing translocation across the epithelial barrier. Together, the concerted actions of both GzmA and GzmB balance cell death mechanisms at the intestinal epithelium to provide optimal control that <em>Salmonella</em> cannot subvert.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"17 6","pages":"Pages 1242-1255"},"PeriodicalIF":7.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11631773/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141976178","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 : 2024-12-01DOI: 10.1016/j.mucimm.2024.08.009
Tao Wu , Sijie Chen , Xinyi Zhu , Jie Ma , Maocai Luo , Yuanhao Wang , Yujie Tian , Qingqing Sun , Xiaohuan Guo , Jianhong Zhang , Xuegong Zhang , Yunping Zhu , Li Wu
The helper-like ILC contains various functional subsets, such as ILC1, ILC2, ILC3 and LTi cells, mediating the immune responses against viruses, parasites, and extracellular bacteria, respectively. Among them, LTi cells are also crucial for the formation of peripheral lymphoid tissues, such as lymph nodes. Our research, along with others’, indicates a high proportion of LTi cells in the fetal ILC pool, which significantly decreases after birth. Conversely, the proportion of non-LTi ILCs increases postnatally, corresponding to the need for LTi cells to mediate lymphoid tissue formation during fetal stages and other ILC subsets to combat diverse pathogen infections postnatally. However, the regulatory mechanism for this transition remains unclear. In this study, we observed a preference for fetal ILC progenitors to differentiate into LTi cells, while postnatal bone marrow ILC progenitors preferentially differentiate into non-LTi ILCs. Particularly, this differentiation shift occurs within the first week after birth in mice. Further analysis revealed that adult ILC progenitors exhibit stronger activation of the Notch signaling pathway compared to fetal counterparts, accompanied by elevated Gata3 expression and decreased Rorc expression, leading to a transition from fetal LTi cell-dominant states to adult non-LTi ILC-dominant states. This study suggests that the body can regulate ILC development by modulating the activation level of the Notch signaling pathway, thereby acquiring different ILC subsets to accommodate the varying demands within the body at different developmental stages.
{"title":"Dynamic regulation of innate lymphoid cell development during ontogeny","authors":"Tao Wu , Sijie Chen , Xinyi Zhu , Jie Ma , Maocai Luo , Yuanhao Wang , Yujie Tian , Qingqing Sun , Xiaohuan Guo , Jianhong Zhang , Xuegong Zhang , Yunping Zhu , Li Wu","doi":"10.1016/j.mucimm.2024.08.009","DOIUrl":"10.1016/j.mucimm.2024.08.009","url":null,"abstract":"<div><div>The helper-like ILC contains various functional subsets, such as ILC1, ILC2, ILC3 and LTi cells, mediating the immune responses against viruses, parasites, and extracellular bacteria, respectively. Among them, LTi cells are also crucial for the formation of peripheral lymphoid tissues, such as lymph nodes. Our research, along with others’, indicates a high proportion of LTi cells in the fetal ILC pool, which significantly decreases after birth. Conversely, the proportion of non-LTi ILCs increases postnatally, corresponding to the need for LTi cells to mediate lymphoid tissue formation during fetal stages and other ILC subsets to combat diverse pathogen infections postnatally. However, the regulatory mechanism for this transition remains unclear. In this study, we observed a preference for fetal ILC progenitors to differentiate into LTi cells, while postnatal bone marrow ILC progenitors preferentially differentiate into non-LTi ILCs. Particularly, this differentiation shift occurs within the first week after birth in mice. Further analysis revealed that adult ILC progenitors exhibit stronger activation of the Notch signaling pathway compared to fetal counterparts, accompanied by elevated <em>Gata3</em> expression and decreased <em>Rorc</em> expression, leading to a transition from fetal LTi cell-dominant states to adult non-LTi ILC-dominant states. This study suggests that the body can regulate ILC development by modulating the activation level of the Notch signaling pathway, thereby acquiring different ILC subsets to accommodate the varying demands within the body at different developmental stages.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"17 6","pages":"Pages 1285-1300"},"PeriodicalIF":7.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142004854","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 : 2024-12-01DOI: 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":"<div><div>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.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"17 6","pages":"Pages 1151-1160"},"PeriodicalIF":7.9,"publicationDate":"2024-12-01","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-01DOI: 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":"<div><div>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 <em>NOX1</em> 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.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"17 6","pages":"Pages 1326-1336"},"PeriodicalIF":7.9,"publicationDate":"2024-12-01","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-01DOI: 10.1016/j.mucimm.2024.08.002
Amber R. Owen , Ana Farias , Anne-Marie Levins , Ziyin Wang , Sophie L. Higham , Matthias Mack , John S. Tregoning , Cecilia Johansson
Respiratory syncytial virus (RSV) can cause severe lower respiratory tract infections. Understanding why some individuals get more serious disease may help with diagnosis and treatment. One possible risk factor underlying severe disease is bacterial exposure before RSV infection. Bacterial exposure has been associated with increased respiratory viral-induced disease severity but the mechanism remains unknown. Respiratory bacterial infections or exposure to their pathogen associated molecular patterns (PAMPs) trigger innate immune inflammation, characterised by neutrophil and inflammatory monocyte recruitment and the production of inflammatory cytokines. We hypothesise that these changes to the lung environment alter the immune response and disease severity during subsequent RSV infection. To test this, we intranasally exposed mice to LPS, LTA or Acinetobacter baumannii (an airway bacterial pathogen) before RSV infection and observed an early induction of disease, measured by weight loss, at days 1–3 after infection. Neutrophils or inflammatory monocytes were not responsible for driving this exacerbated weight loss. Instead, exacerbated disease was associated with increased IL-1α and TNF-α, which orchestrated the recruitment of innate immune cells into the lung. This study shows that exposure to bacterial PAMPs prior to RSV infection increases the expression of IL-1α and TNF-α, which dysregulate the immune response resulting in exacerbated disease.
{"title":"Exposure to bacterial PAMPs before RSV infection exacerbates innate inflammation and disease via IL-1α and TNF-α","authors":"Amber R. Owen , Ana Farias , Anne-Marie Levins , Ziyin Wang , Sophie L. Higham , Matthias Mack , John S. Tregoning , Cecilia Johansson","doi":"10.1016/j.mucimm.2024.08.002","DOIUrl":"10.1016/j.mucimm.2024.08.002","url":null,"abstract":"<div><div>Respiratory syncytial virus (RSV) can cause severe lower respiratory tract infections. Understanding why some individuals get more serious disease may help with diagnosis and treatment. One possible risk factor underlying severe disease is bacterial exposure before RSV infection. Bacterial exposure has been associated with increased respiratory viral-induced disease severity but the mechanism remains unknown. Respiratory bacterial infections or exposure to their pathogen associated molecular patterns (PAMPs) trigger innate immune inflammation, characterised by neutrophil and inflammatory monocyte recruitment and the production of inflammatory cytokines. We hypothesise that these changes to the lung environment alter the immune response and disease severity during subsequent RSV infection. To test this, we intranasally exposed mice to LPS, LTA or <em>Acinetobacter baumannii</em> (an airway bacterial pathogen) before RSV infection and observed an early induction of disease, measured by weight loss, at days 1–3 after infection. Neutrophils or inflammatory monocytes were not responsible for driving this exacerbated weight loss. Instead, exacerbated disease was associated with increased IL-1α and TNF-α, which orchestrated the recruitment of innate immune cells into the lung. This study shows that exposure to bacterial PAMPs prior to RSV infection increases the expression of IL-1α and TNF-α, which dysregulate the immune response resulting in exacerbated disease.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"17 6","pages":"Pages 1184-1198"},"PeriodicalIF":7.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11631774/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141913316","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 : 2024-12-01DOI: 10.1016/j.mucimm.2024.08.005
Jayne E. Wiarda , Adrienne L. Shircliff , Sage R. Becker , Judith B. Stasko , Sathesh K. Sivasankaran , Mark R. Ackermann , Crystal L. Loving
Peyer’s patches (PPs) are B cell-rich sites of intestinal immune induction, yet PP-associated B cell signaling, activation, and differentiation are poorly defined. Single-cell and spatial transcriptomics were completed to study B cells from porcine jejunum and ileum containing PPs. Intestinal locations had distinct immune landscapes, including more follicular B cells in ileum and increased MHC-II-encoding gene expression in jejunal B cells. Despite distinct landscapes, conserved B cell dynamics were detected across intestinal locations, including B cell signaling to CD4+ macrophages that are putative phagocytic, cytotoxic, effector cells and deduced routes of B cell activation/differentiation, including resting B cells migrating into follicles to replicate/divide or differentiate into antibody-secreting cells residing in intestinal crypts. A six-biomarker panel recapitulated transcriptomics findings of B cell phenotypes, frequencies, and spatial locations via ex vivo and in situ staining. Findings convey conserved B cell dynamics across intestinal locations containing PPs, despite location-specific immune environments. Results establish a benchmark of B cell dynamics for understanding intestinal immune induction important to promoting gut/overall health.
佩耶氏斑块（PPs）是肠道免疫诱导中B细胞丰富的部位，但与PPs相关的B细胞信号传导、活化和分化尚不明确。我们完成了单细胞和空间转录组学研究，以研究猪空肠和回肠中含有PPs的B细胞。肠道位置具有不同的免疫景观，包括回肠中更多的滤泡 B 细胞和空肠 B 细胞中更多的 MHC-II 编码基因表达。尽管肠道位置不同，但检测到的 B 细胞动态是一致的，包括 B 细胞向 CD4+ 巨噬细胞发出信号，CD4+ 巨噬细胞是潜在的吞噬细胞、细胞毒性细胞和效应细胞，以及推断出的 B 细胞活化/分化途径，包括静止的 B 细胞迁移到滤泡中复制/分裂或分化成驻留在肠隐窝的分泌抗体的细胞。通过体外和原位染色，一个六种生物标记物面板再现了B细胞表型、频率和空间位置的转录组学发现。研究结果表明，尽管存在特定位置的免疫环境，但在含有PPs的肠道中，B细胞的动态变化是一致的。研究结果为了解对促进肠道/整体健康非常重要的肠道免疫诱导建立了一个 B 细胞动态基准。
{"title":"Conserved B cell signaling, activation, and differentiation in porcine jejunal and ileal Peyer’s patches despite distinct immune landscapes","authors":"Jayne E. Wiarda , Adrienne L. Shircliff , Sage R. Becker , Judith B. Stasko , Sathesh K. Sivasankaran , Mark R. Ackermann , Crystal L. Loving","doi":"10.1016/j.mucimm.2024.08.005","DOIUrl":"10.1016/j.mucimm.2024.08.005","url":null,"abstract":"<div><div>Peyer’s patches (PPs) are B cell-rich sites of intestinal immune induction, yet PP-associated B cell signaling, activation, and differentiation are poorly defined. Single-cell and spatial transcriptomics were completed to study B cells from porcine jejunum and ileum containing PPs. Intestinal locations had distinct immune landscapes, including more follicular B cells in ileum and increased MHC-II-encoding gene expression in jejunal B cells. Despite distinct landscapes, conserved B cell dynamics were detected across intestinal locations, including B cell signaling to <em>CD4<sup>+</sup></em> macrophages that are putative phagocytic, cytotoxic, effector cells and deduced routes of B cell activation/differentiation, including resting B cells migrating into follicles to replicate/divide or differentiate into antibody-secreting cells residing in intestinal crypts. A six-biomarker panel recapitulated transcriptomics findings of B cell phenotypes, frequencies, and spatial locations via <em>ex vivo</em> and <em>in situ</em> staining. Findings convey conserved B cell dynamics across intestinal locations containing PPs, despite location-specific immune environments. Results establish a benchmark of B cell dynamics for understanding intestinal immune induction important to promoting gut/overall health.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"17 6","pages":"Pages 1222-1241"},"PeriodicalIF":7.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141988354","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 : 2024-12-01DOI: 10.1016/j.mucimm.2024.08.007
Sally H. Mohamed , Eliane Vanhoffelen , Man Shun Fu , Pui Hei Lau , Sofia Hain , Laura Seldeslachts , Emilie Cosway , Graham Anderson , Laura McCulloch , Greetje Vande Velde , Rebecca A. Drummond
PLX5622 is a small molecular inhibitor of the CSF1 receptor (CSF1R) and is widely used to deplete macrophages within the central nervous system (CNS). We investigated the impact of PLX5622 treatment in wild-type C57BL/6 mice and discovered that one-week treatment with PLX5622 was sufficient to deplete interstitial macrophages in the lung and brain-infiltrating Ly6Clow patrolling monocytes, in addition to CNS-resident macrophages. These cell types were previously indicated to act as infection reservoirs for the pathogenic fungus Cryptococcus neoformans. We found that PLX5622-treated mice had significantly reduced fungal lung infection and reduced extrapulmonary dissemination to the CNS but not to the spleen or liver. Fungal lung infection mapped to MHCIIhi interstitial lung macrophages, which underwent significant expansion during infection following monocyte replenishment and not local division. Although PLX5622 depleted CNS infiltrating patrolling monocytes, these cells did not accumulate in the fungal-infected CNS following pulmonary infection. In addition, Nr4a1-deficient mice, which lack patrolling monocytes, had similar control and dissemination of C. neoformans infection to wild-type controls. PLX5622 did not directly affect CD4 T-cell responses, or significantly affect production of antibody in the lung during infection. However, we found that mice lacking lymphocytes had reduced numbers of MHCIIhi interstitial macrophages in the lung, which correlated with reduced infection load. Accordingly, PLX5622 treatment did not alter fungal burdens in the lungs of lymphocyte-deficient mice. Our data demonstrate that PLX5622 may help reduce lung burden of pathogenic fungi that utilise CSF1R-dependent myeloid cells as infection reservoirs, an effect which is dependent on the presence of lymphocytes.
{"title":"CSF1R inhibition by PLX5622 reduces pulmonary fungal infection by depleting MHCIIhi interstitial lung macrophages","authors":"Sally H. Mohamed , Eliane Vanhoffelen , Man Shun Fu , Pui Hei Lau , Sofia Hain , Laura Seldeslachts , Emilie Cosway , Graham Anderson , Laura McCulloch , Greetje Vande Velde , Rebecca A. Drummond","doi":"10.1016/j.mucimm.2024.08.007","DOIUrl":"10.1016/j.mucimm.2024.08.007","url":null,"abstract":"<div><div>PLX5622 is a small molecular inhibitor of the CSF1 receptor (CSF1R) and is widely used to deplete macrophages within the central nervous system (CNS). We investigated the impact of PLX5622 treatment in wild-type C57BL/6 mice and discovered that one-week treatment with PLX5622 was sufficient to deplete interstitial macrophages in the lung and brain-infiltrating Ly6C<sup>low</sup> patrolling monocytes, in addition to CNS-resident macrophages. These cell types were previously indicated to act as infection reservoirs for the pathogenic fungus <em>Cryptococcus neoformans</em>. We found that PLX5622-treated mice had significantly reduced fungal lung infection and reduced extrapulmonary dissemination to the CNS but not to the spleen or liver. Fungal lung infection mapped to MHCII<sup>hi</sup> interstitial lung macrophages, which underwent significant expansion during infection following monocyte replenishment and not local division. Although PLX5622 depleted CNS infiltrating patrolling monocytes, these cells did not accumulate in the fungal-infected CNS following pulmonary infection. In addition, Nr4a1-deficient mice, which lack patrolling monocytes, had similar control and dissemination of <em>C. neoformans</em> infection to wild-type controls. PLX5622 did not directly affect CD4 T-cell responses, or significantly affect production of antibody in the lung during infection. However, we found that mice lacking lymphocytes had reduced numbers of MHCII<sup>hi</sup> interstitial macrophages in the lung, which correlated with reduced infection load. Accordingly, PLX5622 treatment did not alter fungal burdens in the lungs of lymphocyte-deficient mice. Our data demonstrate that PLX5622 may help reduce lung burden of pathogenic fungi that utilise CSF1R-dependent myeloid cells as infection reservoirs, an effect which is dependent on the presence of lymphocytes.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"17 6","pages":"Pages 1256-1272"},"PeriodicalIF":7.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142018080","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 : 2024-12-01DOI: 10.1016/j.mucimm.2024.07.010
Yulan Ye , Changqin Liu , Ruijin Wu , Dengfeng Kang , Han Gao , Huiying Lv , Zhongsheng Feng , Yanhong Shi , Zhanju Liu , Liang Chen
Period circadian clock 2 (PER2) is involved in the pathogenesis of various inflammatory and autoimmune diseases. However, there are gaps in our understanding of the role of PER2 in regulating CD4+ T cells beyond its time-keeping function in ulcerative colitis (UC) pathogenesis. Our findings revealed PER2 was predominantly expressed in CD4+ T cells, while it was significantly decreased in the inflamed mucosa and peripheral blood CD4+ T cells of UC patients compared with that in Crohn’s disease (CD) patients and healthy controls (HC). Notably, PER2 expression was significantly recovered in UC patients in remission (R-UC) compared to that in active UC patients (A-UC) but not in CD patients. It was negatively correlated with the Ulcerative Colitis Endoscopic Index of Severity (UCEIS), Crohn’s Disease Activity Index (CDAI), Simple Endoscopic Score for Crohn’s disease (SES-CD), and C-reactive protein (CRP), respectively. Overexpression of PER2 markedly inhibited IFN-γ production in UC CD4+ T cells. RNA-seq analysis showed that overexpression of PER2 could repress the expression of a disintegrin and metalloproteinase 12 (ADAM12), a costimulatory molecule that determines Th1 cell fate. Mechanistically, cleavage under targets and tagmentation (CUT&Tag) analysis revealed that PER2 down-regulated ADAM12 expression by reducing its binding activity, thereby suppressing IFN-γ production in UC CD4+ T cells. Additionally, our data further demonstrated that ADAM12 was upregulated in CD4+ T cells and inflamed mucosa of A-UC patients compared to HC. Our study reveals a critical role of PER2 in regulating CD4+ T cell differentiation and highlights its potential as a therapeutic target for UC treatment.
昼夜节律周期钟 2（PER2）参与了多种炎症和自身免疫性疾病的发病机制。然而，除了在溃疡性结肠炎（UC）发病机制中的计时功能外，我们对PER2在调控CD4+ T细胞中的作用的认识还存在差距。我们的研究结果显示，PER2 主要在 CD4+ T 细胞中表达，而与克罗恩病（CD）患者和健康对照组（HC）相比，PER2 在 UC 患者炎症粘膜和外周血 CD4+ T 细胞中的表达明显减少。值得注意的是，与活动期 UC 患者（A-UC）相比，缓解期 UC 患者（R-UC）的 PER2 表达明显恢复，但 CD 患者的 PER2 表达没有恢复。它分别与溃疡性结肠炎内镜下严重程度指数（UCEIS）、克罗恩病活动指数（CDAI）、克罗恩病简易内镜评分（SES-CD）和 C 反应蛋白（CRP）呈负相关。过表达 PER2 能明显抑制 UC CD4+ T 细胞产生 IFN-γ。RNA-seq分析表明，过表达PER2可抑制崩解素和金属蛋白酶12（ADAM12）的表达，ADAM12是一种决定Th1细胞命运的成本刺激分子。从机理上讲，靶标下裂解和标记（CUT&Tag）分析表明，PER2 通过降低 ADAM12 的结合活性来下调其表达，从而抑制 UC CD4+ T 细胞中 IFN-γ 的产生。此外，我们的数据还进一步表明，与 HC 相比，A-UC 患者 CD4+ T 细胞和炎症粘膜中 ADAM12 表达上调。我们的研究揭示了 PER2 在调节 CD4+ T 细胞分化中的关键作用，并强调了其作为 UC 治疗靶点的潜力。
{"title":"Circadian clock component PER2 negatively regulates CD4+ T cell IFN-γ production in ulcerative colitis","authors":"Yulan Ye , Changqin Liu , Ruijin Wu , Dengfeng Kang , Han Gao , Huiying Lv , Zhongsheng Feng , Yanhong Shi , Zhanju Liu , Liang Chen","doi":"10.1016/j.mucimm.2024.07.010","DOIUrl":"10.1016/j.mucimm.2024.07.010","url":null,"abstract":"<div><div>Period circadian clock 2 (PER2) is involved in the pathogenesis of various inflammatory and autoimmune diseases. However, there are gaps in our understanding of the role of PER2 in regulating CD4<sup>+</sup> T cells beyond its time-keeping function in ulcerative colitis (UC) pathogenesis. Our findings revealed PER2 was predominantly expressed in CD4<sup>+</sup> T cells, while it was significantly decreased in the inflamed mucosa and peripheral blood CD4<sup>+</sup> T cells of UC patients compared with that in Crohn’s disease (CD) patients and healthy controls (HC). Notably, PER2 expression was significantly recovered in UC patients in remission (R-UC) compared to that in active UC patients (A-UC) but not in CD patients. It was negatively correlated with the Ulcerative Colitis Endoscopic Index of Severity (UCEIS), Crohn’s Disease Activity Index (CDAI), Simple Endoscopic Score for Crohn’s disease (SES-CD), and C-reactive protein (CRP), respectively. Overexpression of PER2 markedly inhibited IFN-γ production in UC CD4<sup>+</sup> T cells. RNA-seq analysis showed that overexpression of PER2 could repress the expression of a disintegrin and metalloproteinase 12 (ADAM12), a costimulatory molecule that determines Th1 cell fate. Mechanistically, cleavage under targets and tagmentation (CUT&Tag) analysis revealed that PER2 down-regulated ADAM12 expression by reducing its binding activity, thereby suppressing IFN-γ production in UC CD4<sup>+</sup> T cells. Additionally, our data further demonstrated that ADAM12 was upregulated in CD4<sup>+</sup> T cells and inflamed mucosa of A-UC patients compared to HC. Our study reveals a critical role of PER2 in regulating CD4<sup>+</sup> T cell differentiation and highlights its potential as a therapeutic target for UC treatment.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"17 6","pages":"Pages 1161-1173"},"PeriodicalIF":7.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141889716","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 : 2024-12-01DOI: 10.1016/j.mucimm.2024.08.001
Yiran Li , Shilpi Singh , Haley A. Breckenridge , Tracy X. Cui , Thomas M. Vigil , Jordan E. Kreger , Jing Lei , Harrison K.A. Wong , Peter Sajjakulnukit , Xiaofeng Zhou , J. Kelley Bentley , Costas A. Lyssiotis , Richard M. Mortensen , Marc B. Hershenson
Itaconate was initially identified as an antimicrobial compound produced by myeloid cells. Beyond its antimicrobial role, itaconate may also serve as a crucial metabolic and immune modulator. We therefore examined the roles of aconitate decarboxylase 1 (Acod1) and itaconate in house dust mite (HDM)-sensitized and −challenged mice, a model of T helper 2 (Th2)-driven allergic airways disease. HDM treatment induced lung Acod1 mRNA expression and bronchoalveolar lavage (BAL) itaconate levels in wild-type C57BL/6 mice. Acod1 knockout mice (Acod1-KO) with negligible BAL itaconate showed heightened HDM-induced type 2 cytokine expression, increased serum IgE, and enhanced recruitment of Th2 cells in the lung, indicating a shift towards a more pronounced Th2 immune response. Acod1-KO mice also showed increased eosinophilic airway inflammation and hyperresponsiveness. Experiments in chimeric mice demonstrated that bone marrow from Acod1-KO mice is sufficient to increase type 2 cytokine expression in wild-type mice, and that restitution of bone marrow from wild type mice attenuates mRNA expression of Th2 cytokines in Acod1-KO mice. Specific deletion of Acod1 in lysozyme-secreting macrophages (LysM-cre+Acod1flox/flox) recapitulated the exaggerated phenotype observed in whole-body Acod1-KO mice. Adoptive transfer of Acod1-KO bone marrow-derived macrophages also increased lung mRNA expression of Th2 cytokines. In addition, treatment of Th2-polarized CD4 cells with itaconate impeded Th2 cell differentiation, as shown by reduced expression of Gata3 and decreased release of IL-5 and IL-13. Finally, public datasets of human samples show lower Acod1 expression in subjects with allergic asthma, consistent with a protective role of itaconate in asthma pathogenesis. Together, these data suggest that itaconate plays a protective, immunomodulatory role in limiting airway type 2 inflammation after allergen challenge by attenuating T cell responses.
{"title":"Itaconate suppresses house dust mite-induced allergic airways disease and Th2 cell differentiation","authors":"Yiran Li , Shilpi Singh , Haley A. Breckenridge , Tracy X. Cui , Thomas M. Vigil , Jordan E. Kreger , Jing Lei , Harrison K.A. Wong , Peter Sajjakulnukit , Xiaofeng Zhou , J. Kelley Bentley , Costas A. Lyssiotis , Richard M. Mortensen , Marc B. Hershenson","doi":"10.1016/j.mucimm.2024.08.001","DOIUrl":"10.1016/j.mucimm.2024.08.001","url":null,"abstract":"<div><div>Itaconate was initially identified as an antimicrobial compound produced by myeloid cells. Beyond its antimicrobial role, itaconate may also serve as a crucial metabolic and immune modulator. We therefore examined the roles of aconitate decarboxylase 1 (Acod1) and itaconate in house dust mite (HDM)-sensitized and −challenged mice, a model of T helper 2 (Th2)-driven allergic airways disease. HDM treatment induced lung <em>Acod1</em> mRNA expression and bronchoalveolar lavage (BAL) itaconate levels in wild-type C57BL/6 mice. Acod1 knockout mice (Acod1-KO) with negligible BAL itaconate showed heightened HDM-induced type 2 cytokine expression, increased serum IgE, and enhanced recruitment of Th2 cells in the lung, indicating a shift towards a more pronounced Th2 immune response. Acod1-KO mice also showed increased eosinophilic airway inflammation and hyperresponsiveness. Experiments in chimeric mice demonstrated that bone marrow from Acod1-KO mice is sufficient to increase type 2 cytokine expression in wild-type mice, and that restitution of bone marrow from wild type mice attenuates mRNA expression of Th2 cytokines in Acod1-KO mice. Specific deletion of Acod1 in lysozyme-secreting macrophages (<em>LysM</em>-cre<sup>+</sup><em>Acod1</em><sup>flox/flox</sup>) recapitulated the exaggerated phenotype observed in whole-body Acod1-KO mice. Adoptive transfer of Acod1-KO bone marrow-derived macrophages also increased lung mRNA expression of Th2 cytokines. In addition, treatment of Th2-polarized CD4 cells with itaconate impeded Th2 cell differentiation, as shown by reduced expression of Gata3 and decreased release of IL-5 and IL-13. Finally, public datasets of human samples show lower <em>Acod1</em> expression in subjects with allergic asthma, consistent with a protective role of itaconate in asthma pathogenesis. Together, these data suggest that itaconate plays a protective, immunomodulatory role in limiting airway type 2 inflammation after allergen challenge by attenuating T cell responses.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"17 6","pages":"Pages 1174-1183"},"PeriodicalIF":7.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141988355","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 : 2024-12-01DOI: 10.1016/j.mucimm.2024.08.003
Anna Andrusaite , Jennifer Lewis , Annika Frede , Andrew Farthing , Verena Kästele , Jennifer Montgomery , Allan Mowat , Elizabeth Mann , Simon Milling
Conventional dendritic cells (cDC) are central to maintaining the balance between protective immune responses and tolerance to harmless antigens, especially in the intestine. Short chain fatty acids (SCFAs) such as butyrate play critical roles in regulating intestinal immunity, but the underlying mechanisms remain unclear. Here we demonstrate that microbiota-derived butyrate alters intestinal cDC populations in vivo resulting in decreased numbers of the cDC2 lineage. By establishing a novel in vitro culture model, we show that butyrate has a direct and selective ability to repress the development of cDC2 from cDC precursors, an effect that is independent of G-protein coupled receptors (GPCRs) and is due to inhibition of histone deacetylase 3. Finally, cDC derived from pre-cDC in the presence of butyrate in vitro express lower levels of costimulatory molecules and have a decreased ability to prime naïve T cells. Together, our data show that butyrate affects the developmental trajectory of cDC, selectively repressing the cDC2 lineage and reducing their ability to stimulate T cells. These properties may help explain the ability of butyrate to maintain homeostasis in the intestine.
传统树突状细胞（cDC）是维持保护性免疫反应与无害抗原耐受性之间平衡的核心，尤其是在肠道中。丁酸盐等短链脂肪酸（SCFAs）在调节肠道免疫中发挥着关键作用，但其潜在机制仍不清楚。在这里，我们证明了微生物群衍生的丁酸盐会改变体内肠道 cDC 群体，导致 cDC2 系的数量减少。通过建立一种新型体外培养模型，我们发现丁酸盐具有直接和选择性抑制 cDC 前体发育成 cDC2 的能力，这种作用与 G 蛋白偶联受体（GPCR）无关，而是由于抑制了组蛋白去乙酰化酶 3。最后，在丁酸盐存在的情况下，从体外前 cDC 衍生出的 cDC 表达的成本刺激分子水平较低，对幼稚 T 细胞的刺激能力下降。总之，我们的数据表明，丁酸盐影响了 cDC 的发育轨迹，选择性地抑制了 cDC2 系，降低了它们刺激 T 细胞的能力。这些特性可能有助于解释丁酸盐维持肠道平衡的能力。
{"title":"Microbiota-derived butyrate inhibits cDC development via HDAC inhibition, diminishing their ability to prime T cells","authors":"Anna Andrusaite , Jennifer Lewis , Annika Frede , Andrew Farthing , Verena Kästele , Jennifer Montgomery , Allan Mowat , Elizabeth Mann , Simon Milling","doi":"10.1016/j.mucimm.2024.08.003","DOIUrl":"10.1016/j.mucimm.2024.08.003","url":null,"abstract":"<div><div>Conventional dendritic cells (cDC) are central to maintaining the balance between protective immune responses and tolerance to harmless antigens, especially in the intestine. Short chain fatty acids (SCFAs) such as butyrate play critical roles in regulating intestinal immunity, but the underlying mechanisms remain unclear. Here we demonstrate that microbiota-derived butyrate alters intestinal cDC populations <em>in vivo</em> resulting in decreased numbers of the cDC2 lineage. By establishing a novel <em>in vitro</em> culture model, we show that butyrate has a direct and selective ability to repress the development of cDC2 from cDC precursors, an effect that is independent of G-protein coupled receptors (GPCRs) and is due to inhibition of histone deacetylase 3. Finally, cDC derived from pre-cDC in the presence of butyrate <em>in vitro</em> express lower levels of costimulatory molecules and have a decreased ability to prime naïve T cells. Together, our data show that butyrate affects the developmental trajectory of cDC, selectively repressing the cDC2 lineage and reducing their ability to stimulate T cells. These properties may help explain the ability of butyrate to maintain homeostasis in the intestine.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"17 6","pages":"Pages 1199-1211"},"PeriodicalIF":7.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11631772/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141982795","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}
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