Examinando por Autor "Santander, Cecilio"

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Human intestinal pro-inflammatory CD11chighCCR2+CX3CR1+ macrophages, but not their tolerogenic CD11c−CCR2−CX3CR1− counterparts, are expanded in inflammatory bowel disease
(Springer Nature, 2018) Bernardo, David; Marin, Alicia C; Fernández-Tomé, Samuel; Montalban-Arqués, Ana; Carrasco, A; Tristan, E; Ortega Moreno, Lorena; Mora-Gutierrez, Irene; Diaz-Guerra, A; Caminero-Fernández, R; Miranda, P; Casals, F; Caldas, M; Jiménez, M; Casabona, Sergio; de la Morena, F; Esteve, M; Santander, Cecilio; Chaparro, María; Gisbert, Javier P.
Although macrophages (Mϕ) maintain intestinal immune homoeostasis, there is not much available information about their subset composition, phenotype and function in the human setting. Human intestinal Mϕ (CD45+HLA-DR+CD14+CD64+) can be divided into subsets based on the expression of CD11c, CCR2 and CX3CR1. Monocyte-like cells can be identified as CD11chighCCR2+CX3CR1+ cells, a phenotype also shared by circulating CD14+ monocytes. On the contrary, their Mϕ-like tissue-resident counterparts display a CD11c−CCR2−CX3CR1− phenotype. CD11chigh monocyte-like cells produced IL-1β, both in resting conditions and after LPS stimulation, while CD11c− Mϕ-like cells produced IL-10. CD11chigh pro-inflammatory monocyte-like cells, but not the others, were increased in the inflamed colon from patients with inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis. Tolerogenic IL-10-producing CD11c− Mϕ-like cells were generated from monocytes following mucosal conditioning. Finally, the colonic mucosa recruited circulating CD14+ monocytes in a CCR2-dependent manner, being such capacity expanded in IBD. Mϕ subsets represent, therefore, transition stages from newly arrived pro-inflammatory monocyte-like cells (CD11chighCCR2+CX3CR1+) into tolerogenic tissue-resident (CD11c−CCR2−CX3CR1−) Mϕ-like cells as reflected by the mucosal capacity to recruit circulating monocytes and induce CD11c− Mϕ. The process is nevertheless dysregulated in IBD, where there is an increased migration and accumulation of pro-inflammatory CD11chigh monocyte-like cells.
Immunomodulatory E ect of Gut Microbiota-Derived Bioactive Peptides on Human Immune System from Healthy Controls and Patients with Inflammatory Bowel Disease
(MDPI, 2019) Fernández-Tomé, Samuel; Marin, Alicia C; Ortega Moreno, Lorena; Baldan-Martin, Montse; Mora-Gutierrez, Irene; Lanas-Gimeno, Aitor; Moreno-Monteagudo, Jose Andrés; Santander, Cecilio; Sánchez, Borja; Chaparro, María; Gisbert, Javier P.; Bernardo, David
Bioactive peptides secreted by probiotic Bifidobacterium longum (peptide B7) and opportunistic pathogen Bacteroides fragilis (peptide B12) modulate the intestinal cytokine milieu in health. Here, we characterized their capacity to modulate both the mucosal cytokine production and the phenotype of circulating antigen presenting cells (APCs) in active inflammatory bowel disease (IBD). The IBD mucosa produced higher levels of pro-inflammatory cytokines referred to healthy controls (HCs). Peptides B7 and B12, however, did not ameliorate the mucosal cytokine milieu in IBD. Human circulating APCs (B-cells, monocytes, plasmacytoid dendritic cells (pDCs), and conventional dendritic cells (cDCs)) were characterized by flow cytometry in presence/absence of the peptides. Circulating B-cells, monocytes, and cDCs from IBD patients were more activated than those from HCs. Peptide B7, but not B12, decreased CCR2 expression on all APC subsets from HC, but not IBD patients. Moreover, both peptides tend to further increase their pro-inflammatory profile in IBD. In summary, IBD patients display mucosal and circulating APC pro-inflammatory properties. Peptide B7 immunomodulatory capacity elicited over circulating APCs from HC, but not IBD patients, suggests the presence of disrupted modulatory mechanisms for this peptide in IBD. Future studies should address the effect of bacteria-derived immunomodulatory peptides in non-inflamed (quiescent) IBD patients.
Long Non-Coding RNA Signatures in the Ileum and Colon of Crohn’s Disease Patients and Effect of Anti-TNF-alpha Treatment on Their Modulation
(MDPI, 2023) Baldan-Martin, Montse; Rubín de Célix, Cristina; Orejudo, Macarena; Ortega Moreno, Lorena; Fernández-Tomé, Samuel; Soleto, Irene; Ramírez, Cristina; Arroyo, Ricardo; Fernández, Paloma; Santander, Cecilio; Moreno-Monteagudo, Jose Andrés; Casanova, María José; Casals, Fernando; Casabona, Sergio; Becerro, Irene; Lozano, Juan J; Aransay, Ana Maria; Chaparro, María; Gisbert, Javier P.
Biological therapies only benefit one-third of patients with Crohn’s disease (CD). For this reason, a deeper understanding of the mechanisms by which biologics elicit their effect on intestinal mucosa is needed. Increasing evidence points toward the involvement of long noncoding RNAs (lncRNAs) in the pathogenesis of CD, although their role remains poorly studied. We aimed to characterize lncRNA profiles in the ileum and colon from CD patients and evaluate the effect of anti-TNF-α treatment on their transcription. Terminal ileum and left colon samples from 30 patients (active CD = 10, quiescent CD = 10, and healthy controls (HCs) = 10) were collected for RNA-seq. The patients were classified according to endoscopic activity. Furthermore, biopsies were cultured with infliximab, and their transcriptome was determined by Illumina gene expression array. A total of 678 differentially expressed lncRNAs between the terminal ileum and left colon were identified in HCs, 438 in patients with quiescent CD, and 468 in patients with active CD. Additionally, we identified three new lncRNAs in the ileum associated with CD activity. No differences were observed when comparing the effect of infliximab according to intestinal location, presence of disease (CD vs. HC), and activity (active vs. quiescent). The expression profiles of lncRNAs are associated with the location of intestinal tissue, being very different in the ileum and colon. The presence of CD and disease activity are associated with the differential expression of lncRNAs. No modulatory effect of infliximab has been observed in the lncRNA transcriptome.
Lunasin Peptide is a Modulator of the Immune Response in the Human Gastrointestinal Tract
(Wiley, 2021-04-22) Fernández-Tomé, Samuel; Indiano-Romacho, Pedro; Mora-Gutiérrez, Irene; Pérez-Rodríguez, Leticia; Ortega Moreno, Lorena; Marin, Alicia C; Baldán-Martín, Montse; Moreno-Monteagudo, Jose Andrés; Santander, Cecilio; Chaparro, María; Hernández-Ledesma, Blanca; Gisbert P., Javier; Bernardo, David
Introduction: Lunasin is a soybean bioactive peptide with a variety of beneficial properties against chronic disorders. However, its effect in human primary intestinal cells remains unknown. Hence, this study aims to characterize its ex vivo biological activity in the human intestinal mucosa. Methods and Results: Human intestinal biopsies, obtained from healthy controls, are ex vivo conditioned with lunasin both in the presence/absence of lipopolysaccharide (LPS). Peptide maintains its stability during biopsy culture by HPLC-MS/MS analysis. Lunasin is bioactive in the human mucosa, as it induces IL-1𝜷, TNF-𝜶, IL-17A, CCL2, and PGE2/COX-2 gene expression together with an increased expression of tolerogenic IL-10 and TGF𝜷, while it also downregulates the expression of iNOS and subunit p65 from NF-𝜿B. Indeed, lunasin also abrogates the LPS-induced pro-inflammatory response, downregulating IL-17A, IFN𝜸, and IL-8 expression, and inducing IL-10 and TGF𝜷 expression. These results are also mirrored in the cell-free culture supernatants at the protein level by Multiplex. Moreover, lunasin further induces a regulatory phenotype and function on human intestinal conventional dendritic cell and macrophage subsets as assessed by flow cytometry. Conclusions: We hereby have characterized lunasin as an immunomodulatory peptide with potential capacity to prevent immune and inflammatory-mediated disorders in the human gastrointestinal tract.
Peptides encrypted in the human intestinal microbial-exoproteome as novel biomarkers and immunomodulatory compounds in the gastrointestinal tract
(Elsevier, 2019-01) Fernández-Tomé, Samuel; Montalban-Arqués, Ana; Díaz-Guerra, Alba; Galván-Román, JM; Marin, Alicia C; Mora-Gutiérrez, Irene; Ortega Moreno, Lorena; Santander, Cecilio; Sánchez, Borja; Chaparro, María; P. Gisbert, Javier; Bernardo, David
Peptides encrypted in the intestinal microbial-exoproteome mediate the host-microbiota crosstalk, which is disrupted in inflammatory bowel disease (IBD). Here, the MAHMI database was used for the identification of 20 novel intestinal bacterial peptides. Our results revealed that serum IgA levels directed towards the peptides, but not IgG, discriminated healthy controls from IBD patients. Indeed, they also differentiated patients with ulcerative colitis from Crohńs disease and, within them, patients with and without intestinal inflammation. All peptides were immunomodulatory as they changed the intestinal cytokine milieu following human lamina propria mononuclear cells culture (with/out LPS), revealing a Bifidobacterium longum subsp. longum peptide with the highest tolerogenic properties. Therefore, bacterial peptides encrypted in the human gut metaproteome may have utility as non-invasive biomarkers to aid on IBD diagnosis and monitoring. These peptides also display immunomodulatory effects on the intestinal mucosa revealing them as novel functional compounds for non-drug therapeutic strategies in IBD
Profiling of Human Circulating Dendritic Cells and Monocyte Subsets Discriminates Between Type and Mucosal Status in Patients With Inflammatory Bowel Disease
(2021) Ortega Moreno, Lorena; Fernández-Tomé, Samuel; Chaparro, María; Marin, Alicia C; Mora-Gutierrez, Irene; Santander, Cecilio; Baldan-Martin, Montse; Gisbert, Javier P.; Bernardo, David
[Background]: Intestinal dendritic cells (DC) and macrophages drive disease progression in patients with inflammatory bowel disease (IBD). We aimed to characterize the activation and homing profile of human circulating DC and monocyte subsets in healthy control patients (CP) and IBD patients.