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PROVIDER: PRJNA1036586 | ENA |
REPOSITORIES: ENA
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Project description:Lipocalin-2 expression identifies an immuno-regulatory intestinal neutrophil population during GVHD
| PRJNA943060 | ENA
Project description:Acute graft-versus-host disease (aGVHD) is a life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT). Strategies to promote intestinal tissue tolerance during aGVHD may improve patient outcomes. Using single-cell RNA-sequencing, we identified a Lipocalin-2 (LCN2)-expressing neutrophil population in mice with intestinal aGVHD. Transfer of LCN2-overexpressing neutrophils or treatment with recombinant LCN2 reduced aGVHD-severity, while the lack of epithelial or hematopoietic LCN2 enhanced aGVHD severity and caused microbiome alterations. Mechanistically, LCN2 induced IGF-1R signaling in macrophages via the LCN2 receptor Slc22A17, which increased IL-10 production while reducing MHC-II expression. Transfer of LCN2-pretreated macrophages reduced aGVHD severity. LCN2-treatment did not reduce graft-versus-leukemia effects. In aGVHD patients LCN2 expression correlated with IL-10 expression in intestinal biopsies. We identified a novel intestinal LCN2+ neutrophil population that reduces aGVHD-severity by decreasing MHC-II expression while increasing IL-10 production in macrophages. Administration of LCN2 presents a novel approach against aGVHD to be tested in clinical trials.
2024-02-19 | GSE227064 | GEO
Project description:Gastrointestinal (GI) tract graft versus host disease (GVHD) is a major complication after allogeneic hematopoietic stem cell transplantation (HSCT) and is attributable to dysregulation that occurs between the effector and regulatory arms of the immune system. Whereas regulatory T cells have a primary role in counterbalancing GVHD-induced inflammation, identifying and harnessing other pathways that promote immune tolerance remains a major goal in this disease. Herein, we have identified interleukin 34 (IL-34) as a tissue-intrinsic regulatory cytokine that is able to mitigate the severity of GVHD within the GI tract. Specifically, we observed that absence of recipient IL-34 production exacerbated GVHD lethality, promoted intestinal epithelial cell death, and compromised barrier integrity. Mechanistically, the absence of host IL-34 skewed donor macrophages towards a proinflammatory phenotype and augmented the accumulation of pathogenic CD4+ GM-CSF+ T cells within the colon. Conversely, the administration of recombinant IL-34 significantly reduced GVHD mortality and inflammation in the GI tract which was dependent upon the expression of apolipoprotein E (ApoE) in donor macrophages. Complementary genetic and imaging approaches demonstrated that intestinal epithelial cells were the biologically relevant source of IL-34. Colonic biopsies from patients with GVHD also revealed expression of IL-34 in intestinal epithelial cells, as well as ApoE in lamina propria macrophages, validating similar cellular localization in humans. Thus, these studies define IL-34 as an intestinal epithelial-derived cytokine that regulates macrophage polarization in an ApoE-dependent manner, positioning this cytokine as a key regulator of GVHD in the GI tract and a potential therapeutic target for amelioration of this disease.
2025-07-09 | GSE252891 | GEO
Project description:The symptoms of infectious diarrheal disease are mediated by the interplay between the host and pathogen. Campylobacter jejuni is the leading bacterial cause of diarrhea worldwide due to its near-ubiquitous zoonotic association with poultry. One of the outstanding questions is what factors drive the intestinal inflammation during the development of C. jejuni-mediated disease. Specifically, it is not known the extent to which the bacteria are responsible for the diarrheal symptoms via cell necrosis, or whether there is immune cell recruitment prior to tissue damage. To determine the stepwise process of inflammation that leads to diarrhea, we used a piglet ligated intestinal loop model to study the intestinal environment in response to C. jejuni. Pigs were chosen due to the anatomical similarity of the porcine intestine to the human intestine, as the basis of disease modeling is to understand the process of human disease. Using immunoassays and proteomic approaches, we found that neutrophils are most likely the predominant cell type recruited to the intestines of C. jejuni infected animals. In the lumen of the intestine, a number of neutrophil related proteins increased during C. jejuni infection, including proteins related to neutrophil migration (elastase and MMP9), actin reorganization and bacterial uptake (Cdc42, WAVE-2, and Arp2/3), and antimicrobial proteins (lipocalin-2, myeloperoxidase, S100A8, and S100A9). The appearance of neutrophils also corresponds with increases of both IL-8 and TNF-a. Compared to infection with the C. jejuni wild-type strain, infection with the noninvasive C. jejuni ∆ciaD mutant resulted in a blunted inflammatory response, with less inflammatory cytokines and neutrophil markers. These findings indicate that intestinal inflammation is driven by C. jejuni virulence, and that resident intestinal cells precipitate the inflammatory response. Using this new disease model, we have developed a platform to study the early immune events during C. jejuni infection.
2020-10-07 | GSE147629 | GEO
Project description:Lipocalin 24p3 (24p3) is a neutrophil secondary granule protein. 24p3 is also a siderocalin, which binds several bacterial siderophores. It was therefore proposed that synthesis and secretion of 24p3 by stimulated macrophages or release of 24p3 upon neutrophil degranulation sequesters iron-laden siderophores to attenuate bacterial growth. Accordingly, 24p3-deficient mice are susceptible to bacterial pathogens whose siderophores would normally be chelated by 24p3. Specific granule deficiency (SGD) is a rare congenital disorder characterized by complete absence of proteins in secondary granules. Neutrophils from SGD patients, who are prone to bacterial infections, lack normal functions but the potential role of 24p3 in neutrophil dysfunction in SGD is not known. Here we show that neutrophils from 24p3-deficient mice are defective in many neutrophil functions. Specifically, neutrophils in 24p3-deficient mice do not extravasate to sites of infection and are defective for chemotaxis. A transcriptome analysis revealed that genes that control cytoskeletal reorganization are selectively suppressed in 24p3-deficient neutrophils. Additionally, small regulatory RNAs (miRNAs) that control upstream regulators of cytoskeletal proteins are also increased in 24p3-deficient neutrophils. Further, 24p3-deficient neutrophils failed to phagocytose bacteria, which may account for the enhanced sensitivity of 24p3-deficient mice to both intracellular (Listeria monocytogenes) and extracellular (Candida albicans, Staphylococcus aureus) pathogens. Interestingly, Listeria does not secrete siderophores and additionally, the siderophore secreted by Candida is not sequestered by 24p3. Therefore, the heightened sensitivity of 24p3-deficient mice to these pathogens is not due to sequestration of siderophores limiting iron availability, but is a consequence of impaired neutrophil function. Key words: Lipocalin, 24p3, neutrophils, cell motility, chemotaxis, MIRNA-362-3p To address the role of lipocalin 2 in regulating miRNA expression profiling in neutrophils derived from mouse bone marrow, we performed microarray analysis of miRNAs in wild type (N=2) and lcn2 knockout (N=2) neutrophils.
2013-01-31 | E-GEOD-43890 | biostudies-arrayexpress
Project description:During inflammation immune cells can induce endothelial activation and angiogenesis by cytokines and other mediators1,2. The inhibition of inflammation-associated angiogenesis ameliorates inflammatory diseases by reducing the recruitment of tissue infiltrating leukocytes3-5. However, there is limited evidence on initial mechanisms of both processes. Here we show that angiogenesis precedes leukocyte infiltration during graft-versus-host disease (GVHD) and experimental colitis. A key feature of GVHD is the incompletely understood organ tropism to skin, liver and the intestines. We found that angiogenesis initiates GVHD in target organs whereas in non-target organs no angiogenesis and no subsequent inflammation occur, suggesting a previously unrecognized role of the endothelium in GVHD organ tropism. The initiation phase of angiogenesis was not associated to classical endothelial cell (EC) activation signs, such as Vegfa/VEGFR1+2 upregulation or increased adhesion molecule expression. In gene array- and proteomic analyses, we found significant metabolic and cytoskeleton changes in ECs leading to profoundly higher deformation in real-time deformability cytometry6. Our results demonstrate that metabolic changes trigger enhanced migratory and proliferating potential of ECs during the initiation of angiogenesis in GVHD target organs. Our study adds evidence to the hypothesis that angiogenesis can initiate inflammation and provides novel insight in pathophysiology and tropism of GVHD.
2017-01-31 | PXD004606 | Pride
Project description:Tuberculosis results from an interaction between a chronically persistent pathogen counteracted by IFN-g-mediated immune responses. Modulation of IFN-g signaling could therefore constitute a major immune evasion mechanism for M. tuberculosis. SOCS1 plays a major role in the inhibition of IFN-g-mediated responses. We found that M. tuberculosis infection stimulates SOCS1 expression in mouse and human myeloid cells. Significantly higher levels of SOCS1 were induced after in vitro or in vivo infection with virulent M. tuberculosis-than with attenuated M. bovis BCG. Different innate and adaptive immune mechanisms participated in infection-induced SOCS1 expression. SOCS1 hampered M. tuberculosis clearance both in macrophages and during murine infection in vivo. On the other hand, SOCS1 protected the host from an infection-induced inflammation. Despite SOCS1 expression, mycobacteria-infected macrophages were not tolerant to IFN-g. Instead, an impaired IFN-g secretion by macrophages, associated to lower responses to IL-12, accounted for the increased mycobacterial intracellular growth in presence of SOCS1. SOCS1 attenuated the expression of the majority of genes modulated by infection of macrophages (6,1% of the transcriptome), indicating the relevance of the molecule in the outcome of infection with M. tuberculosis. We suggest that SOCS1 is expressed during M. tuberculosis infection to establish a successful chronic infection, and dampen inflammatory damage. Difference in genotype and TB infection comparison Relative gene expressions were determined by normalized intensity values. GeneSpring analysis was performed using the Treg transcriptome data with following comparisons: no GvHD d90 versus no GvHD d150, no GvHD d90 versus acute GvHD, no GvHD d150 versus chronic GvHD, acute GvHD versus chronic GvHD, acute GvHD versus GvHD d90 and chronic GvHD versus GvHD d150 (Figure 2). Cut-off was a transcript fold change of +2 or -2 in at least one comparison. Student´s t-test was used to identify significant expression changes.
2012-01-18 | E-GEOD-23508 | biostudies-arrayexpress
Project description:Lipocalin 24p3 (24p3) is a neutrophil secondary granule protein. 24p3 is also a siderocalin, which binds several bacterial siderophores. It was therefore proposed that synthesis and secretion of 24p3 by stimulated macrophages or release of 24p3 upon neutrophil degranulation sequesters iron-laden siderophores to attenuate bacterial growth. Accordingly, 24p3-deficient mice are susceptible to bacterial pathogens whose siderophores would normally be chelated by 24p3. Specific granule deficiency (SGD) is a rare congenital disorder characterized by complete absence of proteins in secondary granules. Neutrophils from SGD patients, who are prone to bacterial infections, lack normal functions but the potential role of 24p3 in neutrophil dysfunction in SGD is not known. Here we show that neutrophils from 24p3-deficient mice are defective in many neutrophil functions. Specifically, neutrophils in 24p3-deficient mice do not extravasate to sites of infection and are defective for chemotaxis. A transcriptome analysis revealed that genes that control cytoskeletal reorganization are selectively suppressed in 24p3-deficient neutrophils. Additionally, small regulatory RNAs (miRNAs) that control upstream regulators of cytoskeletal proteins are also increased in 24p3-deficient neutrophils. Further, 24p3-deficient neutrophils failed to phagocytose bacteria, which may account for the enhanced sensitivity of 24p3-deficient mice to both intracellular (Listeria monocytogenes) and extracellular (Candida albicans, Staphylococcus aureus) pathogens. Interestingly, Listeria does not secrete siderophores and additionally, the siderophore secreted by Candida is not sequestered by 24p3. Therefore, the heightened sensitivity of 24p3-deficient mice to these pathogens is not due to sequestration of siderophores limiting iron availability, but is a consequence of impaired neutrophil function. Key words: Lipocalin, 24p3, neutrophils, cell motility, chemotaxis, MIRNA-362-3p To address the role of lipocalin 2 in unstimulated and fMLP-stimulated neutrophils derived from mouse bone marrow, we performed micorarray analysis of gene expression in unstimulated wild type (N=3), unstimulated lcn2 knockout (N=3), fMLP-stimulated wild type (N=2) and fMLP-stimulated lcn2 knockout (N=2) neutrophils. Upon stimulation, neutrophils were treated by fMLP at 10 micromolar for 20 minutes at 37 centigrade.
2013-01-31 | E-GEOD-43889 | biostudies-arrayexpress
Project description:Graft-versus-host disease (GvHD) is critical complication after allogeneic hematopoietic stem cell transplantation (HSCT). The immunosuppressants given to patients undergoing allogeneic HSCT disturb the microbiome and the host immune system, potentially leading to dysbiosis and inflammation. The intestinal microbiome is a target for the development of novel therapies for GvHD. We determined the effect of the combination of tacrolimus (FK506) and Lactobacillus acidophilus on GvHD.
2021-05-11 | GSE174214 | GEO