Pub Date : 2024-10-01DOI: 10.1016/j.mucimm.2024.06.002
Corneal wound healing in diabetic patients is usually delayed and accompanied by excessive inflammation. However, the underlying cellular and molecular mechanisms remain poorly understood. Here, we found that somatostatin (SST), an immunosuppressive peptide produced by corneal nerve fibers, was significantly reduced in streptozotocin-induced diabetic mice. In addition, we discovered that topical administration of exogenous SST significantly improved re-epithelialization and nerve regeneration following diabetic corneal epithelial abrasion. Further analysis showed that topical SST significantly reduced the expression of injury inflammation-related genes, inhibited neutrophil infiltration, and shifted macrophage polarization from pro-inflammatory M1 to anti-inflammatory M2 in diabetic corneas' healing. Moreover, the application of L-817,818, an agonist of the SST receptor type 5 subtype, significantly reduced the inflammatory response following epithelial injury and markedly improved the process of re-epithelialization and nerve regeneration in mice. Taken together, these data suggest that activation of the SST-SST receptor type 5 pathway significantly ameliorates diabetes-induced abnormalities in corneal wound repair in mice. Targeting this pathway may provide a novel strategy to restore impaired corneal wound closure and nerve regeneration in diabetic patients.
{"title":"Activation of the SST-SSTR5 signaling pathway enhances corneal wound healing in diabetic mice","authors":"","doi":"10.1016/j.mucimm.2024.06.002","DOIUrl":"10.1016/j.mucimm.2024.06.002","url":null,"abstract":"<div><div>Corneal wound healing in diabetic patients is usually delayed and accompanied by excessive inflammation. However, the underlying cellular and molecular mechanisms remain poorly understood. Here, we found that somatostatin (SST), an immunosuppressive peptide produced by corneal nerve fibers, was significantly reduced in streptozotocin-induced diabetic mice. In addition, we discovered that topical administration of exogenous SST significantly improved re-epithelialization and nerve regeneration following diabetic corneal epithelial abrasion. Further analysis showed that topical SST significantly reduced the expression of injury inflammation-related genes, inhibited neutrophil infiltration, and shifted macrophage polarization from pro-inflammatory M1 to anti-inflammatory M2 in diabetic corneas' healing. Moreover, the application of L-817,818, an agonist of the SST receptor type 5 subtype, significantly reduced the inflammatory response following epithelial injury and markedly improved the process of re-epithelialization and nerve regeneration in mice. Taken together, these data suggest that activation of the SST-SST receptor type 5 pathway significantly ameliorates diabetes-induced abnormalities in corneal wound repair in mice. Targeting this pathway may provide a novel strategy to restore impaired corneal wound closure and nerve regeneration in diabetic patients.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"17 5","pages":"Pages 858-870"},"PeriodicalIF":7.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141311210","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.2024.06.004
T lymphocytes and myeloid cells express the immunoglobulin-like glycoprotein cluster of differentiation (CD)101, notably in the gut. Here, we investigated the cell-specific functions of CD101 during dextran sulfate sodium (DSS)-induced colitis and Salmonella enterica Typhimurium infection. Similar to conventional CD101−/− mice, animals with a regulatory T cell-specific Cd101 deletion developed more severe intestinal pathology than littermate controls in both models. While the accumulation of T helper 1 cytokines in a CD101-deficient environment entertained DSS-induced colitis, it impeded the replication of Salmonella as revealed by studying CD101−/− x interferon-g−/− mice. Moreover, CD101-expressing neutrophils were capable to restrain Salmonella infection in vitro and in vivo. Both cell-intrinsic and -extrinsic mechanisms of CD101 contributed to the control of bacterial growth and spreading. The CD101-dependent containment of Salmonella infection required the expression of Irg-1 and Nox2 and the production of itaconate and reactive oxygen species. The level of intestinal microbial antigens in the sera of inflammatory bowel disease patients correlated inversely with the expression of CD101 on myeloid cells, which is in line with the suppression of CD101 seen in mice following DSS application or Salmonella infection. Thus, depending on the experimental or clinical setting, CD101 helps to limit inflammatory insults or bacterial infections due to cell type-specific modulation of metabolic, immune-regulatory, and anti-microbial pathways.
{"title":"Cell type-specific modulation of metabolic, immune-regulatory, and anti-microbial pathways by CD101","authors":"","doi":"10.1016/j.mucimm.2024.06.004","DOIUrl":"10.1016/j.mucimm.2024.06.004","url":null,"abstract":"<div><div>T lymphocytes and myeloid cells express the immunoglobulin-like glycoprotein cluster of differentiation (CD)101, notably in the gut. Here, we investigated the cell-specific functions of CD101 during dextran sulfate sodium (DSS)-induced colitis and <em>Salmonella enterica</em> Typhimurium infection. Similar to conventional CD101<sup>−/−</sup> mice, animals with a regulatory T cell-specific <em>Cd101</em> deletion developed more severe intestinal pathology than littermate controls in both models. While the accumulation of T helper 1 cytokines in a CD101-deficient environment entertained DSS-induced colitis, it impeded the replication of <em>Salmonella</em> as revealed by studying CD101<sup>−/−</sup> x interferon-g<sup>−/−</sup> mice. Moreover, CD101-expressing neutrophils were capable to restrain <em>Salmonella</em> infection <em>in vitro</em> and <em>in vivo</em>. Both cell-intrinsic and -extrinsic mechanisms of CD101 contributed to the control of bacterial growth and spreading. The CD101-dependent containment of <em>Salmonella</em> infection required the expression of <em>Irg-1</em> and <em>Nox2</em> and the production of itaconate and reactive oxygen species. The level of intestinal microbial antigens in the sera of inflammatory bowel disease patients correlated inversely with the expression of CD101 on myeloid cells, which is in line with the suppression of CD101 seen in mice following DSS application or <em>Salmonella</em> infection. Thus, depending on the experimental or clinical setting, CD101 helps to limit inflammatory insults or bacterial infections due to cell type-specific modulation of metabolic, immune-regulatory, and anti-microbial pathways.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"17 5","pages":"Pages 892-910"},"PeriodicalIF":7.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141432276","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.2024.06.009
Intestinal stromal cells (SCs), which synthesize the extracellular matrix that gives the mucosa its structure, are newly appreciated to play a role in mucosal inflammation. Here, we show that human intestinal vimentin+CD90+smooth muscle actin− SCs synthesize retinoic acid (RA) at levels equivalent to intestinal epithelial cells, a function in the human intestine previously attributed exclusively to epithelial cells. Crohn’s disease SCs (Crohn’s SCs), however, synthesized markedly less RA than SCs from healthy intestine (normal SCs). We also show that microbe-stimulated Crohn’s SCs, which are more inflammatory than stimulated normal SCs, induced less RA-regulated differentiation of mucosal dendritic cells (DCs) (circulating pre-DCs and monocyte-derived DCs), leading to the generation of more potent inflammatory interferon-γhi/interleukin-17hi T cells than normal SCs. Explaining these results, Crohn’s SCs expressed more DHRS3, a retinaldehyde reductase that inhibits retinol conversion to retinal and, thus, synthesized less RA than normal SCs. These findings uncover a microbe–SC–DC crosstalk in which luminal microbes induce Crohn’s disease SCs to initiate and perpetuate inflammation through impaired synthesis of RA.
肠道基质细胞（SCs）合成细胞外基质，赋予粘膜结构，新近被认为在粘膜炎症中发挥作用。在这里，我们展示了人类肠道波形蛋白+CD90+SMA- SCs合成维甲酸（RA）的水平与肠道上皮细胞相当，而这种功能在人类肠道中以前被认为是上皮细胞的专有功能。然而，克罗恩病 SCs（克罗恩 SCs）合成的视黄酸明显少于健康肠道 SCs（正常 SCs）。我们还发现，微生物刺激的克罗恩病 SCs 比刺激的正常 SCs 具有更强的炎症性，它们诱导的由 RA 调节的粘膜 DCS（循环前 DCs 和单核细胞衍生 DCs）分化较少，从而产生了比正常 SCs 更强的炎症性 IFN-γhi/IL-17hi T 细胞。为了解释这些结果，克罗恩病 SCs 表达了更多的 DHRS3（一种抑制视黄醇转化为视黄醛的视黄醛还原酶），因此合成的 RA 比正常 SCs 少。这些发现揭示了微生物-SC-DC 之间的串联作用，其中管腔微生物诱导克罗恩病 SCs 通过受损的 RA 合成启动和延续炎症。
{"title":"Human intestinal stromal cells promote homeostasis in normal mucosa but inflammation in Crohn’s disease in a retinoic acid–deficient manner","authors":"","doi":"10.1016/j.mucimm.2024.06.009","DOIUrl":"10.1016/j.mucimm.2024.06.009","url":null,"abstract":"<div><div>Intestinal stromal cells (SCs), which synthesize the extracellular matrix that gives the mucosa its structure, are newly appreciated to play a role in mucosal inflammation. Here, we show that human intestinal vimentin<sup>+</sup>CD90<sup>+</sup>smooth muscle actin<sup>−</sup> SCs synthesize retinoic acid (RA) at levels equivalent to intestinal epithelial cells, a function in the human intestine previously attributed exclusively to epithelial cells. Crohn’s disease SCs (Crohn’s SCs), however, synthesized markedly less RA than SCs from healthy intestine (normal SCs). We also show that microbe-stimulated Crohn’s SCs, which are more inflammatory than stimulated normal SCs, induced less RA-regulated differentiation of mucosal dendritic cells (DCs) (circulating pre-DCs and monocyte-derived DCs), leading to the generation of more potent inflammatory interferon-γ<sup>hi</sup>/interleukin-17<sup>hi</sup> T cells than normal SCs. Explaining these results, Crohn’s SCs expressed more DHRS3, a retinaldehyde reductase that inhibits retinol conversion to retinal and, thus, synthesized less RA than normal SCs. These findings uncover a microbe–SC–DC crosstalk in which luminal microbes induce Crohn’s disease SCs to initiate and perpetuate inflammation through impaired synthesis of RA.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"17 5","pages":"Pages 958-972"},"PeriodicalIF":7.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141469516","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.2024.06.008
Citrobacter rodentium models infection with enteropathogenic Escherichia coli and ulcerative colitis (UC). While C57BL/6 (C57) mice recover, C3H/HeN (C3H) mice succumb to infection, partially due to increased colonic neutrophil elastase activity, also seen in UC patients; however, the underlying cause was unknown. Here, we found that bone marrow, blood, and colonic C57 neutrophils expressed (CD)11bHi and reached the infected colonic lumen, where they underwent productive NETosis. In contrast, while the number of C3H neutrophils increased in the bone marrow, blood, and colon, they remained CD11bLo and got trapped in the submucosa, away from C. rodentium, where they underwent harmful NETosis. CD11bLo neutrophils in C3H mice infected with CRi9, which triggers expression of neutrophil chemoattractants, reached the colonization site, resulting in host survival. UC patient neutrophils also displayed decreased levels of the activation/differentiation markers CD16/CXCR4. These results, suggesting that neutrophil malfunction contributes to exacerbated colitis, provide insight for future therapeutic prospects.
{"title":"Impaired neutrophil migration underpins host susceptibility to infectious colitis","authors":"","doi":"10.1016/j.mucimm.2024.06.008","DOIUrl":"10.1016/j.mucimm.2024.06.008","url":null,"abstract":"<div><div><em>Citrobacter rodentium</em> models infection with enteropathogenic <em>Escherichia coli</em> and ulcerative colitis (UC). While C57BL/6 (C57) mice recover, C3H/HeN (C3H) mice succumb to infection, partially due to increased colonic neutrophil elastase activity, also seen in UC patients; however, the underlying cause was unknown. Here, we found that bone marrow, blood, and colonic C57 neutrophils expressed (CD)11b<sup>Hi</sup> and reached the infected colonic lumen, where they underwent productive NETosis. In contrast, while the number of C3H neutrophils increased in the bone marrow, blood, and colon, they remained CD11b<sup>Lo</sup> and got trapped in the submucosa, away from <em>C. rodentium</em>, where they underwent harmful NETosis. CD11b<sup>Lo</sup> neutrophils in C3H mice infected with CR<sub>i9</sub>, which triggers expression of neutrophil chemoattractants, reached the colonization site, resulting in host survival. UC patient neutrophils also displayed decreased levels of the activation/differentiation markers CD16/CXCR4. These results, suggesting that neutrophil malfunction contributes to exacerbated colitis, provide insight for future therapeutic prospects.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"17 5","pages":"Pages 939-957"},"PeriodicalIF":7.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141469517","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.2024.07.006
Huijuan Le , Yanyan Wang , Jiefei Zhou , Dan Li , Zizhen Gong , Fangxinxing Zhu , Jian Wang , Chunyan Tian , Wei Cai , Jin Wu
Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease in preterm infants and the most common cause of neonatal death, whereas the molecular mechanism of intestinal injury remains unclear accompanied by deficiency of effective therapeutic approaches. GIT2 (G-protein-coupled receptor kinase interacting proteins 2) can affect innate and adaptive immunity and has been involved in multiple inflammatory disorders. In this study, we investigated whether GIT2 participates in the pathogenesis of NEC. Here we found that intestinal Git2 gene expression was significantly increased in NEC patients and NEC mice, which positively correlated with the tissue damage severity, and Git2 deficiency could potently protect against NEC development in mice. Mechanistically, Git2 gene knockout dramatically increased the recruitment of MDSCs in the intestine, and in vivo depletion of MDSCs almost completely abrogated the protective effect of Git2 deficiency on NEC. Moreover, Git2 deficiency induced MDSCs intestinal accumulation mainly relied on CXCL1/CXCL12 signaling, as evidenced by the significant increment of CXCL1 and CXCL12 levels in intestinal epithelium of Git2-/- mice and dramatically decrease of MDSCs accumulation in intestine as well as increase of NEC severity upon treatment of CXCL1/CXCL12 pathway inhibitors. In addition, Git2 deficiency induced up-regulation of CXCL1 and CXCL12 is at least partially mediated through activating NF-κB signaling. Thus, our findings suggest that GIT2 is involved in the pathogenesis of NEC, and targeting GIT2 may be a potential preventive and therapeutic approach for NEC.
坏死性小肠结肠炎（NEC）是早产儿的一种严重胃肠道疾病，也是新生儿死亡的最常见原因，但肠道损伤的分子机制仍不清楚，也缺乏有效的治疗方法。GIT2（G-蛋白偶联受体激酶相互作用蛋白 2）可影响先天性免疫和适应性免疫，并参与多种炎症性疾病。本研究探讨了 GIT2 是否参与了 NEC 的发病机制。我们发现，肠道 Git2 基因在 NEC 患者和 NEC 小鼠中的表达明显增加，与组织损伤的严重程度呈正相关，Git2 基因缺失可有效防止小鼠 NEC 的发生。从机理上讲，Git2 基因敲除可显著增加肠道内 MDSCs 的募集，而体内 MDSCs 的耗竭几乎完全减弱了 Git2 缺乏对 NEC 的保护作用。此外，Git2缺陷诱导的MDSCs肠道聚集主要依赖于CXCL1/CXCL12信号转导，这表现在Git2-/-小鼠肠上皮细胞中CXCL1和CXCL12水平显著升高，CXCL1/CXCL12通路抑制剂治疗后MDSCs肠道聚集显著减少，NEC严重程度增加。此外，Git2 缺乏诱导的 CXCL1 和 CXCL12 上调至少部分是通过激活 NF-κB 信号介导的。因此，我们的研究结果表明，GIT2 参与了 NEC 的发病机制，靶向 GIT2 可能是一种潜在的 NEC 预防和治疗方法。
{"title":"Git2 deficiency promotes MDSCs recruitment in intestine via NF-κB-CXCL1/CXCL12 pathway and ameliorates necrotizing enterocolitis","authors":"Huijuan Le , Yanyan Wang , Jiefei Zhou , Dan Li , Zizhen Gong , Fangxinxing Zhu , Jian Wang , Chunyan Tian , Wei Cai , Jin Wu","doi":"10.1016/j.mucimm.2024.07.006","DOIUrl":"10.1016/j.mucimm.2024.07.006","url":null,"abstract":"<div><div>Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease in preterm infants and the most common cause of neonatal death, whereas the molecular mechanism of intestinal injury remains unclear accompanied by deficiency of effective therapeutic approaches. GIT2 (G-protein-coupled receptor kinase interacting proteins 2) can affect innate and adaptive immunity and has been involved in multiple inflammatory disorders. In this study, we investigated whether GIT2 participates in the pathogenesis of NEC. Here we found that intestinal <em>Git2</em> gene expression was significantly increased in NEC patients and NEC mice, which positively correlated with the tissue damage severity, and <em>Git2</em> deficiency could potently protect against NEC development in mice. Mechanistically, <em>Git2</em> gene knockout dramatically increased the recruitment of MDSCs in the intestine, and <em>in vivo</em> depletion of MDSCs almost completely abrogated the protective effect of <em>Git2</em> deficiency on NEC. Moreover, <em>Git2</em> deficiency induced MDSCs intestinal accumulation mainly relied on CXCL1/CXCL12 signaling, as evidenced by the significant increment of CXCL1 and CXCL12 levels in intestinal epithelium of <em>Git2</em><sup>-/-</sup> mice and dramatically decrease of MDSCs accumulation in intestine as well as increase of NEC severity upon treatment of CXCL1/CXCL12 pathway inhibitors. In addition, <em>Git2</em> deficiency induced up-regulation of CXCL1 and CXCL12 is at least partially mediated through activating NF-κB signaling. Thus, our findings suggest that GIT2 is involved in the pathogenesis of NEC, and targeting GIT2 may be a potential preventive and therapeutic approach for NEC.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"17 5","pages":"Pages 1060-1071"},"PeriodicalIF":7.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141792938","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.2024.05.007
Mycobacterium tuberculosis (Mtb)-infected neutrophils are often found in the airways of patients with active tuberculosis (TB), and excessive recruitment of neutrophils to the lung is linked to increased bacterial burden and aggravated pathology in TB. The basis for the permissiveness of neutrophils for Mtb and the ability to be pathogenic in TB has been elusive. Here, we identified metabolic and functional features of neutrophils that contribute to their permissiveness in Mtb infection. Using single-cell metabolic and transcriptional analyses, we found that neutrophils in the Mtb-infected lung displayed elevated mitochondrial metabolism, which was largely attributed to the induction of activated neutrophils with enhanced metabolic activities. The activated neutrophil subpopulation was also identified in the lung granulomas from Mtb-infected non-human primates. Functionally, activated neutrophils harbored more viable bacteria and displayed enhanced lipid uptake and accumulation. Surprisingly, we found that interferon-γ promoted the activation of lung neutrophils during Mtb infection. Lastly, perturbation of lipid uptake pathways selectively compromised Mtb survival in activated neutrophils. These findings suggest that neutrophil heterogeneity and metabolic diversity are key to their permissiveness for Mtb and that metabolic pathways in neutrophils represent potential host-directed therapeutics in TB.
{"title":"Metabolically active neutrophils represent a permissive niche for Mycobacterium tuberculosis","authors":"","doi":"10.1016/j.mucimm.2024.05.007","DOIUrl":"10.1016/j.mucimm.2024.05.007","url":null,"abstract":"<div><div><em>Mycobacterium tuberculosis</em> (Mtb)-infected neutrophils are often found in the airways of patients with active tuberculosis (TB), and excessive recruitment of neutrophils to the lung is linked to increased bacterial burden and aggravated pathology in TB. The basis for the permissiveness of neutrophils for Mtb and the ability to be pathogenic in TB has been elusive. Here, we identified metabolic and functional features of neutrophils that contribute to their permissiveness in Mtb infection. Using single-cell metabolic and transcriptional analyses, we found that neutrophils in the Mtb-infected lung displayed elevated mitochondrial metabolism, which was largely attributed to the induction of activated neutrophils with enhanced metabolic activities. The activated neutrophil subpopulation was also identified in the lung granulomas from Mtb-infected non-human primates. Functionally, activated neutrophils harbored more viable bacteria and displayed enhanced lipid uptake and accumulation. Surprisingly, we found that interferon-γ promoted the activation of lung neutrophils during Mtb infection. Lastly, perturbation of lipid uptake pathways selectively compromised Mtb survival in activated neutrophils. These findings suggest that neutrophil heterogeneity and metabolic diversity are key to their permissiveness for Mtb and that metabolic pathways in neutrophils represent potential host-directed therapeutics in TB.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"17 5","pages":"Pages 825-842"},"PeriodicalIF":7.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141284213","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.2024.06.005
The increased risk of food allergy in infants with atopic dermatitis (AD) has long been recognized; an epidemiologic phenomenon termed “the atopic march.” Current literature supports the hypothesis that food antigen exposure through the disrupted skin barrier in AD leads to food antigen-specific immunoglobulin E production and food sensitization. However, there is growing evidence that inflammation in the skin drives intestinal remodeling via circulating inflammatory signals, microbiome alterations, metabolites, and the nervous system. We explore how this skin-gut axis helps to explain the link between AD and food allergy beyond sensitization.
{"title":"Atopic dermatitis and food allergy: More than sensitization","authors":"","doi":"10.1016/j.mucimm.2024.06.005","DOIUrl":"10.1016/j.mucimm.2024.06.005","url":null,"abstract":"<div><div>The increased risk of food allergy in infants with atopic dermatitis (AD) has long been recognized; an epidemiologic phenomenon termed “the atopic march.” Current literature supports the hypothesis that food antigen exposure through the disrupted skin barrier in AD leads to food antigen-specific immunoglobulin E production and food sensitization. However, there is growing evidence that inflammation in the skin drives intestinal remodeling via circulating inflammatory signals, microbiome alterations, metabolites, and the nervous system. We explore how this skin-gut axis helps to explain the link between AD and food allergy beyond sensitization.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"17 5","pages":"Pages 1128-1140"},"PeriodicalIF":7.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141437253","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.2024.06.007
Regulatory T cells (Tregs) are well-known to mediate peripheral tolerance at homeostasis, and there is a growing appreciation for their role in modulating infectious disease immunity. Following acute and chronic infections, Tregs can restrict pathogen-specific T cell responses to limit immunopathology. However, it is unclear if Tregs mediate control of pathology and immunity in distal tissue sites during localized infections. We investigated the role of Tregs in immunity and disease in various tissue compartments in the context of “mild” vaginal Zika virus infection. We found that Tregs are critical to generating robust virus-specific CD8 T cell responses in the initial infection site. Further, Tregs limit inflammatory cytokines and immunopathology during localized infection; a dysregulated immune response in Treg-depleted mice leads to increased T cell infiltrates and immunopathology in both the vagina and the central nervous system (CNS). Importantly, these CNS infiltrates are not present at the same magnitude during infection of Treg-sufficient mice, in which there is no CNS immunopathology. Our data suggest that Tregs are necessary to generate a robust virus-specific response at the mucosal site of infection, while Treg-mediated restriction of bystander inflammation limits immunopathology both at the site of infection as well as distal tissue sites.
众所周知，调节性 T 细胞（Treg）在平衡状态下介导外周耐受性，而人们也越来越认识到它们在调节传染病免疫方面的作用。急性和慢性感染后，调节性 T 细胞可限制病原体特异性 T 细胞反应，从而限制免疫病理学。然而，目前还不清楚在局部感染期间，Tregs 是否能介导对远端组织部位病理和免疫的控制。我们以 "轻度 "阴道寨卡病毒（ZIKV）感染为背景，研究了Tregs在不同组织区免疫和疾病中的作用。我们发现，Tregs 对于在初始感染部位产生强大的病毒特异性 CD8 T 细胞反应至关重要。此外，Tregs 还能限制局部感染期间的炎性细胞因子和免疫病理；Treg 缺失的小鼠免疫反应失调会导致阴道和中枢神经系统（CNS）的 T 细胞浸润和免疫病理增加。重要的是，这些中枢神经系统浸润在感染 Treg 充足的小鼠时不会以同样的程度出现，因为在这种情况下不会出现中枢神经系统免疫病理。我们的数据表明，Tregs 是在粘膜感染部位产生强大的病毒特异性反应的必要条件，而 Treg 介导的旁观者炎症限制了感染部位和远端组织部位的免疫病理。
{"title":"Regulatory T cells restrict immunity and pathology in distal tissue sites following a localized infection","authors":"","doi":"10.1016/j.mucimm.2024.06.007","DOIUrl":"10.1016/j.mucimm.2024.06.007","url":null,"abstract":"<div><div>Regulatory T cells (Tregs) are well-known to mediate peripheral tolerance at homeostasis, and there is a growing appreciation for their role in modulating infectious disease immunity. Following acute and chronic infections, Tregs can restrict pathogen-specific T cell responses to limit immunopathology. However, it is unclear if Tregs mediate control of pathology and immunity in distal tissue sites during localized infections. We investigated the role of Tregs in immunity and disease in various tissue compartments in the context of “mild” vaginal Zika virus infection. We found that Tregs are critical to generating robust virus-specific CD8 T cell responses in the initial infection site. Further, Tregs limit inflammatory cytokines and immunopathology during localized infection; a dysregulated immune response in Treg-depleted mice leads to increased T cell infiltrates and immunopathology in both the vagina and the central nervous system (CNS). Importantly, these CNS infiltrates are not present at the same magnitude during infection of Treg-sufficient mice, in which there is no CNS immunopathology. Our data suggest that Tregs are necessary to generate a robust virus-specific response at the mucosal site of infection, while Treg-mediated restriction of bystander inflammation limits immunopathology both at the site of infection as well as distal tissue sites.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"17 5","pages":"Pages 923-938"},"PeriodicalIF":7.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141440697","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.2024.06.010
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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号