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1.
mSphere ; : e0047824, 2024 Aug 14.
Artículo en Inglés | MEDLINE | ID: mdl-39140728

RESUMEN

Ascaris is one of the most widespread helminth infections, leading to chronic morbidity in humans and considerable economic losses in pig farming. In addition, pigs are an important reservoir for the zoonotic salmonellosis, where pigs can serve as asymptomatic carriers. Here, we investigated the impact of an ongoing Ascaris infection on the immune response to Salmonella in pigs. We observed higher bacterial burdens in experimentally coinfected pigs compared to pigs infected with Salmonella alone. The impaired control of Salmonella in the coinfected pigs was associated with repressed interferon gamma responses in the small intestine and with the alternative activation of gut macrophages evident in elevated CD206 expression. Ascaris single and coinfection were associated with a rise of CD4-CD8α+FoxP3+ Treg in the lymph nodes draining the small intestine and liver. In addition, macrophages from coinfected pigs showed enhanced susceptibility to Salmonella infection in vitro and the Salmonella-induced monocytosis and tumor necrosis factor alpha production by myeloid cells was repressed in pigs coinfected with Ascaris. Hence, our data indicate that acute Ascaris infection modulates different immune effector functions with important consequences for the control of tissue-invasive coinfecting pathogens.IMPORTANCEIn experimentally infected pigs, we show that an ongoing infection with the parasitic worm Ascaris suum modulates host immunity, and coinfected pigs have higher Salmonella burdens compared to pigs infected with Salmonella alone. Both infections are widespread in pig production and the prevalence of Salmonella is high in endemic regions of human Ascariasis, indicating that this is a clinically meaningful coinfection. We observed the type 2/regulatory immune response to be induced during an Ascaris infection correlates with increased susceptibility of pigs to the concurrent bacterial infection.

2.
Quant Imaging Med Surg ; 14(8): 5973-5982, 2024 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-39144032

RESUMEN

Background: While standard clinical magnetic resonance (MR) enterography can detect inflammatory bowel disease, it is of limited value in deciding between medical versus surgical treatment. Alternatively, intestinal MR elastography has the potential to contribute additional information to therapeutic decision-making; however, the influence of bowel distension by oral contrast agent on viscoelastic tissue properties remains elusive. Therefore, we aimed to investigate the influence of oral contrast agent-induced bowel distension on the viscoelastic properties of the terminal ileum in healthy volunteers. Methods: In this prospective pilot study, 20 healthy volunteers (33.2±8.2 years; 10 men, 10 women) underwent multifrequency MR elastography using a single-shot spin-echo echo planar imaging sequence at 1.5 Tesla and drive frequencies of 40, 50, 60 and 70 Hz. Maps of shear wave speed (c in ms-1) and loss angle (φ in rad), representing stiffness and viscous properties, respectively, were generated using tomoelastography data processing. The volunteers were scanned before and after ingestion of 1,000 mL of 2% mannitol solution as oral contrast agent. Results: There was no significant difference in terminal ileum biomechanical properties before vs. after ingestion of an oral contrast agent (mean c: 1.47±0.24 vs. 1.40±0.25 ms-1 with P=0.37; mean φ: 0.70±0.12 rad vs. 0.68±0.12 rad with P=0.61). Moreover, there was no statistically significant correlation between MR elastography parameters before and after the ingestion of oral contrast (c: r=0.22, P=0.36; φ: r=0.24, P=0.30). Conclusions: The results of this study suggest that bowel distension for intestinal MR elastography has no systematic effect on the biomechanical tissue properties of the terminal ileum determined by MR elastography. Therefore, future study protocols appear feasible with or without oral contrast agents.

4.
Sci Rep ; 14(1): 14919, 2024 06 28.
Artículo en Inglés | MEDLINE | ID: mdl-38942904

RESUMEN

Helminth infections lead to an overdispersion of the parasites in humans as well as in animals. We asked whether early immune responses against migrating Ascaris larvae are responsible for the unequal distribution of worms in natural host populations and thus investigated a susceptible versus a resistant mouse strain. In mice, the roundworm larvae develop until the lung stage and thus early anti-Ascaris immune responses against the migrating larvae in the liver and lung can be deciphered. Our data show that susceptible C57BL/6 mice respond to Ascaris larval migration significantly stronger compared to resistant CBA mice and the anti-parasite reactivity is associated with pathology. Increased eosinophil recruitment was detected in the liver and lungs, but also in the spleen and peritoneal cavity of susceptible mice on day 8 post infection compared to resistant mice. In serum, eosinophil peroxidase levels were significantly higher only in the susceptible mice, indicating functional activity of the recruited eosinophils. This effect was associated with an increased IL-5/IL-13 production by innate lymphoid cells and CD4+ T cells and a pronounced type 2 macrophage polarization in the lungs of susceptible mice. Furthermore, a comparison of wildtype BALB/c and eosinophil-deficient dblGATA-1 BALB/c mice showed that eosinophils were not essential for the early control of migrating Ascaris larvae. In conclusion, in primary infection, a strong local and systemic type 2 immune response during hepato-tracheal helminth larval migration is associated with pathology rather than protection.


Asunto(s)
Ascariasis , Larva , Pulmón , Ratones Endogámicos BALB C , Células Th2 , Animales , Ascariasis/inmunología , Ascariasis/parasitología , Larva/inmunología , Ratones , Células Th2/inmunología , Pulmón/parasitología , Pulmón/inmunología , Pulmón/patología , Ascaris/inmunología , Eosinófilos/inmunología , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Hígado/parasitología , Hígado/inmunología , Hígado/patología , Femenino
5.
Gut ; 2024 Apr 29.
Artículo en Inglés | MEDLINE | ID: mdl-38684238

RESUMEN

OBJECTIVE: Mutations in presenilin genes are the major cause of Alzheimer's disease. However, little is known about their expression and function in the gut. In this study, we identify the presenilins Psen1 and Psen2 as key molecules that maintain intestinal homoeostasis. DESIGN: Human inflammatory bowel disease (IBD) and control samples were analysed for Psen1 expression. Newly generated intestinal epithelium-specific Psen1-deficient, Psen2-deficient and inducible Psen1/Psen2 double-deficient mice were used to dissect the functional role of presenilins in intestinal homoeostasis. RESULTS: Psen1 expression was regulated in experimental gut inflammation and in patients with IBD. Induced deletion of Psen1 and Psen2 in mice caused rapid weight loss and spontaneous development of intestinal inflammation. Mice exhibited epithelial barrier disruption with bacterial translocation and deregulation of key pathways for nutrient uptake. Wasting disease was independent of gut inflammation and dysbiosis, as depletion of microbiota rescued Psen-deficient animals from spontaneous colitis development but not from weight loss. On a molecular level, intestinal epithelial cells lacking Psen showed impaired Notch signalling and dysregulated epithelial differentiation. CONCLUSION: Overall, our study provides evidence that Psen1 and Psen2 are important guardians of intestinal homoeostasis and future targets for barrier-promoting therapeutic strategies in IBD.

6.
J Crohns Colitis ; 18(8): 1305-1318, 2024 Aug 14.
Artículo en Inglés | MEDLINE | ID: mdl-38465390

RESUMEN

BACKGROUND AND AIMS: Fistula formation is a major complication in Crohn's disease [CD] and the role of the immune cell compartment remains to be elucidated. Thus, we compared the immune cell compartment of CD fistula to inflammatory CD colitis using imaging mass cytometry [IMC] and immunofluorescence. METHODS: A 36-marker panel including structural, functional, and lineage markers for use in IMC was established. This panel was applied to analyse paraffin-embedded CD fistula tract [n = 11], CD colitis [n = 10], and colon samples from non-inflamed controls [n = 12]. Computational methods for cell segmentation, dimensionality reduction, and cell type clustering were used to define cell populations for cell frequency, marker distribution, and spatial neighbourhood analysis. Multiplex immunofluorescence was used for higher resolution spatial analysis. RESULTS: Analysis of cell frequencies in CD fistulas compared to CD colitis and control colonic samples revealed a significant increase in neutrophils, effector cytotoxic T cells, and inflammatory macrophages in CD fistula samples, whereas regulatory T cells were decreased. Neutrophils in CD fistula expressed significantly more matrix metalloproteinase 9 [MMP9], correlating with extracellular matrix remodelling. Neighbourhood analysis revealed a strong association between MMP9+ neutrophils and effector cytotoxic T cells in both CD fistulas and colitis. CONCLUSIONS: This study presents the first highly multiplexed single cell analysis of the immune cell compartment of CD fistulas and their spatial context. It links immune cell dynamics, particularly MMP9+ neutrophils, to extracellular matrix remodelling in CD fistulas, offering insights into the complex network of cellular interactions and potential therapeutic targets for CD complications.


Asunto(s)
Enfermedad de Crohn , Enfermedad de Crohn/patología , Enfermedad de Crohn/inmunología , Humanos , Masculino , Femenino , Adulto , Análisis de la Célula Individual/métodos , Citometría de Imagen/métodos , Fístula Intestinal/etiología , Biomarcadores/análisis , Biomarcadores/metabolismo , Persona de Mediana Edad , Estudios de Casos y Controles , Metaloproteinasa 9 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/análisis , Macrófagos/metabolismo , Macrófagos/patología , Macrófagos/inmunología , Neutrófilos/metabolismo , Colitis/patología , Colitis/inmunología , Colon/patología , Colon/diagnóstico por imagen
7.
Sci Signal ; 17(824): eadc9662, 2024 02 20.
Artículo en Inglés | MEDLINE | ID: mdl-38377177

RESUMEN

The IL-6-gp130-STAT3 signaling axis is a major regulator of inflammation. Activating mutations in the gene encoding gp130 and germline gain-of-function mutations in STAT3 (STAT3GOF) are associated with multi-organ autoimmunity, severe morbidity, and adverse prognosis. To dissect crucial cellular subsets and disease biology involved in activated gp130 signaling, the gp130-JAK-STAT3 axis was constitutively activated using a transgene, L-gp130, specifically targeted to T cells. Activating gp130 signaling in T cells in vivo resulted in fatal, early onset, multi-organ autoimmunity in mice that resembled human STAT3GOF disease. Female mice had more rapid disease progression than male mice. On a cellular level, gp130 signaling induced the activation and effector cell differentiation of T cells, promoted the expansion of T helper type 17 (TH17) cells, and impaired the activity of regulatory T cells. Transcriptomic profiling of CD4+ and CD8+ T cells from these mice revealed commonly dysregulated genes and a gene signature that, when applied to human transcriptomic data, improved the segregation of patients with transcriptionally diverse STAT3GOF mutations from healthy controls. The findings demonstrate that increased gp130-STAT3 signaling leads to TH17-driven autoimmunity that phenotypically resembles human STAT3GOF disease.


Asunto(s)
Autoinmunidad , Linfocitos T CD8-positivos , Humanos , Masculino , Femenino , Ratones , Animales , Receptor gp130 de Citocinas/genética , Receptor gp130 de Citocinas/metabolismo , Autoinmunidad/genética , Linfocitos T CD8-positivos/metabolismo , Transducción de Señal , Inflamación , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo
8.
J Neurooncol ; 167(1): 155-167, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38358406

RESUMEN

BACKGROUND: Emerging evidence suggests that treatment of NSCLC brain metastases with immune checkpoint inhibitors (ICIs) is associated with response rates similar to those of extracranial disease. Programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) serves as a predictive biomarker for ICI response. However, the predictive value of brain metastasis-specific (intracranial) PD-L1 TPS is not established. We investigated the role of intra- and extracranial PD-L1 TPS in NSCLC patients treated with ICI following brain metastasis resection. METHODS: Clinical data from NSCLC patients treated with ICI following brain metastasis resection (n = 64) were analyzed. PD-L1 TPS of brain metastases (n = 64) and available matched extracranial tumor tissue (n = 44) were assessed via immunohistochemistry. Statistical analyses included cut point estimation via maximally selected rank statistics, Kaplan-Meier estimates, and multivariable Cox regression analysis for intracranial progression-free survival (icPFS), extracranial progression-free survival (ecPFS), and overall survival (OS). RESULTS: PD-L1 expression was found in 54.7% of brain metastases and 68.2% of extracranial tumor tissues, with a median intra- and extracranial PD-L1 TPS of 7.5% (0 - 50%, IQR) and 15.0% (0 - 80%, IQR), respectively. In matched tissue samples, extracranial PD-L1 TPS was significantly higher than intracranial PD-L1 TPS (p = 0.013). Optimal cut points for intracranial and extracranial PD-L1 TPS varied according to outcome parameter assessed. Notably, patients with a high intracranial PD-L1 TPS (> 40%) exhibited significantly longer icPFS as compared to patients with a low intracranial PD-L1 TPS (≤ 40%). The cut point of 40% for intracranial PD-L1 TPS was independently associated with OS, icPFS and ecPFS in multivariable analyses. CONCLUSION: Our study highlights the potential role of intracranial PD-L1 TPS in NSCLC, which could be used to predict ICI response in cases where extracranial tissue is not available for PD-L1 assessment as well as to specifically predict intracranial response.


Asunto(s)
Neoplasias Encefálicas , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/cirugía , Antígeno B7-H1/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/cirugía , Estudios Retrospectivos
9.
Acta Neuropathol ; 147(1): 8, 2024 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-38175305

RESUMEN

Multiple sclerosis (MS) is a chronic neuroinflammatory disease that involves both white and gray matter. Although gray matter damage is a major contributor to disability in MS patients, conventional clinical magnetic resonance imaging (MRI) fails to accurately detect gray matter pathology and establish a clear correlation with clinical symptoms. Using magnetic resonance elastography (MRE), we previously reported global brain softening in MS and experimental autoimmune encephalomyelitis (EAE). However, it needs to be established if changes of the spatiotemporal patterns of brain tissue mechanics constitute a marker of neuroinflammation. Here, we use advanced multifrequency MRE with tomoelastography postprocessing to investigate longitudinal and regional inflammation-induced tissue changes in EAE and in a small group of MS patients. Surprisingly, we found reversible softening in synchrony with the EAE disease course predominantly in the cortex of the mouse brain. This cortical softening was associated neither with a shift of tissue water compartments as quantified by T2-mapping and diffusion-weighted MRI, nor with leukocyte infiltration as seen by histopathology. Instead, cortical softening correlated with transient structural remodeling of perineuronal nets (PNNs), which involved abnormal chondroitin sulfate expression and microgliosis. These mechanisms also appear to be critical in humans with MS, where tomoelastography for the first time demonstrated marked cortical softening. Taken together, our study shows that neuroinflammation (i) critically affects the integrity of PNNs in cortical brain tissue, in a reversible process that correlates with disease disability in EAE, (ii) reduces the mechanical integrity of brain tissue rather than leading to water accumulation, and (iii) shows similar spatial patterns in humans and mice. These results raise the prospect of leveraging MRE and quantitative MRI for MS staging and monitoring treatment in affected patients.


Asunto(s)
Diagnóstico por Imagen de Elasticidad , Encefalomielitis Autoinmune Experimental , Esclerosis Múltiple , Humanos , Animales , Ratones , Enfermedades Neuroinflamatorias , Imagen por Resonancia Magnética , Imagen de Difusión por Resonancia Magnética , Encefalomielitis Autoinmune Experimental/diagnóstico por imagen , Agua
10.
J Crohns Colitis ; 18(1): 121-133, 2024 Jan 27.
Artículo en Inglés | MEDLINE | ID: mdl-37565754

RESUMEN

BACKGROUND AND AIMS: Pain is a cardinal symptom in inflammatory bowel disease [IBD]. An important structure in the transduction of pain signalling is the myenteric plexus [MP]. Nevertheless, IBD-associated infiltration of the MP by immune cells lacks in-depth characterisation. Herein, we decipher intra- and periganglionic immune cell infiltrations in Crohn´s disease [CD] and ulcerative colitis [UC] and provide a comparison with murine models of colitis. METHODS: Full wall specimens of surgical colon resections served to examine immune cell populations by either conventional immuno-histochemistry or immunofluorescence followed by either bright field or confocal microscopy. Results were compared with equivalent examinations in various murine models of intestinal inflammation. RESULTS: Whereas the MP morphology was not significantly altered in IBD, we identified intraganglionic IBD-specific B cell- and monocyte-dominant cell infiltrations in CD. In contrast, UC-MPs were infiltrated by CD8+ T cells and revealed a higher extent of ganglionic cell apoptosis. With regard to the murine models of intestinal inflammation, the chronic dextran sulphate sodium [DSS]-induced colitis model reflected CD [and to a lesser extent UC] best, as it also showed increased monocytic infiltration as well as a modest B cell and CD8+ T cell infiltration. CONCLUSIONS: In CD, MPs were infiltrated by B cells and monocytes. In UC, mostly CD8+ cytotoxic T cells were found. The chronic DSS-induced colitis in the mouse model reflected best the MP-immune cell infiltrations representative for IBD.


Asunto(s)
Colitis Ulcerosa , Colitis , Enfermedad de Crohn , Enfermedades Inflamatorias del Intestino , Animales , Ratones , Colitis Ulcerosa/metabolismo , Enfermedad de Crohn/metabolismo , Plexo Mientérico/metabolismo , Colitis/inducido químicamente , Neurotransmisores/efectos adversos , Dolor , Inflamación
11.
Gut ; 73(2): 282-297, 2024 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-37884352

RESUMEN

OBJECTIVE: We sought to investigate the role of interleukin (IL)-20 in IBD and experimental colitis. DESIGN: Experimental colitis was induced in mice deficient in components of the IL-20 and signal transducer and activator of transcription (STAT)2 signalling pathways. In vivo imaging, high-resolution mini-endoscopy and histology were used to assess intestinal inflammation. We further used RNA-sequencing (RNA-Seq), RNAScope and Gene Ontology analysis, western blot analysis and co-immunoprecipitation, confocal microscopy and intestinal epithelial cell (IEC)-derived three-dimensional organoids to investigate the underlying molecular mechanisms. Results were validated using samples from patients with IBD and non-IBD control subjects by a combination of RNA-Seq, organoids and immunostainings. RESULTS: In IBD, IL20 levels were induced during remission and were significantly higher in antitumour necrosis factor responders versus non-responders. IL-20RA and IL-20RB were present on IECs from patients with IBD and IL-20-induced STAT3 and suppressed interferon (IFN)-STAT2 signalling in these cells. In IBD, experimental dextran sulfate sodium (DSS)-induced colitis and mucosal healing, IECs were the main producers of IL-20. Compared with wildtype controls, Il20-/-, Il20ra-/- and Il20rb-/- mice were more susceptible to experimental DSS-induced colitis. IL-20 deficiency was associated with increased IFN/STAT2 activity in mice and IFN/STAT2-induced necroptotic cell death in IEC-derived organoids could be markedly blocked by IL-20. Moreover, newly generated Stat2ΔIEC mice, lacking STAT2 in IECs, were less susceptible to experimental colitis compared with wildtype controls and the administration of IL-20 suppressed colitis activity in wildtype animals. CONCLUSION: IL-20 controls colitis and mucosal healing by interfering with the IFN/STAT2 death signalling pathway in IECs. These results indicate new directions for suppressing gut inflammation by modulating IL-20-controlled STAT2 signals.


Asunto(s)
Colitis , Enfermedades Inflamatorias del Intestino , Humanos , Animales , Ratones , Mucosa Intestinal/metabolismo , Colitis/metabolismo , Interleucinas/metabolismo , Inflamación/metabolismo , Células Epiteliales/metabolismo , Enfermedades Inflamatorias del Intestino/genética , Sulfato de Dextran/farmacología , Ratones Endogámicos C57BL , Factor de Transcripción STAT2/metabolismo
12.
Mol Cancer Ther ; 23(4): 507-519, 2024 Apr 02.
Artículo en Inglés | MEDLINE | ID: mdl-38159110

RESUMEN

The small-molecule inhibitor of ataxia telangiectasia and Rad3-related protein (ATR), elimusertib, is currently being tested clinically in various cancer entities in adults and children. Its preclinical antitumor activity in pediatric malignancies, however, is largely unknown. We here assessed the preclinical activity of elimusertib in 38 cell lines and 32 patient-derived xenograft (PDX) models derived from common pediatric solid tumor entities. Detailed in vitro and in vivo molecular characterization of the treated models enabled the evaluation of response biomarkers. Pronounced objective response rates were observed for elimusertib monotherapy in PDX, when treated with a regimen currently used in clinical trials. Strikingly, elimusertib showed stronger antitumor effects than some standard-of-care chemotherapies, particularly in alveolar rhabdomysarcoma PDX. Thus, elimusertib has strong preclinical antitumor activity in pediatric solid tumor models, which may translate to clinically meaningful responses in patients.


Asunto(s)
Antineoplásicos , Neoplasias , Niño , Humanos , Ensayos Antitumor por Modelo de Xenoinjerto , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Biomarcadores , Línea Celular Tumoral
13.
Nutrients ; 15(19)2023 Sep 29.
Artículo en Inglés | MEDLINE | ID: mdl-37836505

RESUMEN

INTRODUCTION: The human intestinal tract reacts to extensive resection with spontaneous intestinal adaptation. We analyzed whether gene expression analyses or intestinal permeability (IP) testing could provide biomarkers to describe regulation mechanisms in the intestinal barrier in short bowel syndrome (SBS) patients during adaptive response or treatment with the glucagon-like peptide-2 analog teduglutide. METHODS: Relevant regions of the GLP-2 receptor gene were sequenced. Gene expression analyses and immunohistochemistry were performed from mucosal biopsies. IP was assessed using a carbohydrate oral ingestion test. RESULTS: The study includes 59 SBS patients and 19 controls. Increases in gene expression with teduglutide were received for sucrase-isomaltase, sodium/glucose cotransporter 1, and calcium/calmodulin serine protein kinase. Mannitol recovery was decreased in SBS but elevated with teduglutide (Δ 40%), showed a positive correlation with remnant small bowel and an inverse correlation with parenteral support. CONCLUSIONS: Biomarkers predicting clinical and functional features in human SBS are very limited. Altered specific gene expression was shown for genes involved in nutrient transport but not for genes controlling tight junctions. However, mannitol recovery proved useful in describing the absorptive capacity of the gut during adaptation and treatment with teduglutide.


Asunto(s)
Síndrome del Intestino Corto , Humanos , Síndrome del Intestino Corto/terapia , Intestino Delgado/patología , Péptido 2 Similar al Glucagón , Biomarcadores , Manitol , Fármacos Gastrointestinales/uso terapéutico
14.
Quant Imaging Med Surg ; 13(8): 4792-4805, 2023 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-37581033

RESUMEN

Background: Although there is growing evidence that functional involvement and structural changes of mesenteric adipose tissue (MAT) influence the course of Crohn's disease (CD), its viscoelastic properties remain elusive. Therefore, we aimed to investigate the viscoelastic properties of MAT in CD using magnetic resonance elastography (MRE), providing reference values for CD diagnosis. Methods: In this prospective proof-of-concept study, 31 subjects (CD: n=11; healthy controls: n=20) were consecutively enrolled in a specialized care center for inflammatory bowel diseases (tertiary/quaternary care). Inclusion criteria for the CD patients were a clinically and endoscopically established diagnosis of CD based on the clinical record, absence of other concurrent bowel diseases, scheduled surgery for the following day, and age of at least 18 years. Diagnoses were confirmed by histological analysis of the resected bowel the day after MRE. Subjects were investigated using MRE at 1.5-T with frequencies of 40-70 Hz. To retrieve shear wave speed (SWS), volumes of interest (VOIs) in MAT were drawn adjacent to CD lesions (MATCD) and on the opposite side without adjacent bowel lesions in patients (MATCD_Opp) and controls (MATCTRL). The presented study is not registered in the clinical trial platform. Results: A statistically significant decrease in mean SWS of 7% was found for MATCD_Opp vs. MATCTRL (0.76±0.05 vs. 0.82±0.04 m/s, P=0.012), whereas there was a nonsignificant trend with an 8% increase for MATCD vs. MATCD_Opp (0.82±0.07 vs. 0.76±0.05 m/s, P=0.098) and no difference for MATCD vs. MATCTRL. Preliminary area under the receiver operating characteristic curve (AUC) analysis showed diagnostic accuracy in detecting CD to be excellent for SWS of MATCD_Opp [AUC =0.82; 95% confidence interval (CI): 0.64-0.96] but poor for SWS of MATCD (AUC =0.52; 95% CI: 0.34-0.73). Conclusions: This study demonstrates the feasibility of MRE of MAT and presents preliminary reference values for CD patients and healthy controls. Our results motivate further studies for the biophysical characterization of MAT in inflammatory bowel disease.

15.
Redox Biol ; 64: 102803, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37392516

RESUMEN

Inflammatory bowel disease (IBD) is an immune-mediated gut dysfunction, which might also be associated with an inflammatory phenotype in the liver. It is known that the nutritional intake of omega-3 polyunsaturated fatty acids (n-3 PUFA) is inversely correlated to the severity and occurrence of IBD. In order to investigate whether n-3 PUFA can also reduce liver inflammation and oxidative liver damage due to colon inflammation, we explored the dextran sulfate sodium (DSS)-induced colitis model in wild-type and fat-1 mice with endogenously increased n-3 PUFA tissue content. Besides confirming previous data of alleviated DSS-induced colitis in the fat-1 mouse model, the increase of n-3 PUFA also resulted in a significant reduction of liver inflammation and oxidative damage in colitis-affected fat-1 mice as compared to wild-type littermates. This was accompanied by a remarkable increase of established inflammation-dampening n-3 PUFA oxylipins, namely docosahexaenoic acid-derived 19,20-epoxydocosapentaenoic acid and eicosapentaenoic acid-derived 15-hydroxyeicosapentaenoic acid and 17,18-epoxyeicosatetraenoic acid. Taken together, these observations demonstrate a strong inverse correlation between the anti-inflammatory lipidome derived from n-3 PUFA and the colitis-triggered inflammatory changes in the liver by reducing oxidative liver stress.


Asunto(s)
Colitis , Ácidos Grasos Omega-3 , Enfermedades Inflamatorias del Intestino , Ratones , Animales , Ratones Transgénicos , Ácidos Grasos Omega-3/efectos adversos , Colitis/inducido químicamente , Colitis/genética , Inflamación/genética , Hígado , Estrés Oxidativo
16.
Front Immunol ; 14: 1163198, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37207229

RESUMEN

Background: Fibrostenotic disease is a common complication in Crohn's disease (CD) patients hallmarked by transmural extracellular matrix (ECM) accumulation in the intestinal wall. The prevention and medical therapy of fibrostenotic CD is an unmet high clinical need. Although targeting IL36R signaling is a promising therapy option, downstream mediators of IL36 during inflammation and fibrosis have been incompletely understood. Candidate molecules include matrix metalloproteinases which mediate ECM turnover and are thereby potential targets for anti-fibrotic treatment. Here, we have focused on understanding the role of MMP13 during intestinal fibrosis. Methods: We performed bulk RNA sequencing of paired colon biopsies taken from non-stenotic and stenotic areas of patients with CD. Corresponding tissue samples from healthy controls and CD patients with stenosis were used for immunofluorescent (IF) staining. MMP13 gene expression was analyzed in cDNA of intestinal biopsies from healthy controls and in subpopulations of patients with CD in the IBDome cohort. In addition, gene regulation on RNA and protein level was studied in colon tissue and primary intestinal fibroblasts from mice upon IL36R activation or blockade. Finally, in vivo studies were performed with MMP13 deficient mice and littermate controls in an experimental model of intestinal fibrosis. Ex vivo tissue analysis included Masson's Trichrome and Sirius Red staining as well as evaluation of immune cells, fibroblasts and collagen VI by IF analysis. Results: Bulk RNA sequencing revealed high upregulation of MMP13 in colon biopsies from stenotic areas, as compared to non-stenotic regions of patients with CD. IF analysis confirmed higher levels of MMP13 in stenotic tissue sections of CD patients and demonstrated αSMA+ and Pdpn+ fibroblasts as a major source. Mechanistic experiments demonstrated that MMP13 expression was regulated by IL36R signaling. Finally, MMP13 deficient mice, as compared to littermate controls, developed less fibrosis in the chronic DSS model and showed reduced numbers of αSMA+ fibroblasts. These findings are consistent with a model suggesting a molecular axis involving IL36R activation in gut resident fibroblasts and MMP13 expression during the pathogenesis of intestinal fibrosis. Conclusion: Targeting IL36R-inducible MMP13 could evolve as a promising approach to interfere with the development and progression of intestinal fibrosis.


Asunto(s)
Enfermedad de Crohn , Animales , Ratones , Metaloproteinasa 13 de la Matriz , Enfermedad de Crohn/metabolismo , Colon , Fibrosis , Constricción Patológica , Interleucinas/metabolismo
17.
Int J Mol Sci ; 24(8)2023 Apr 17.
Artículo en Inglés | MEDLINE | ID: mdl-37108564

RESUMEN

The paracaspase MALT1 is a crucial regulator of immune responses in various cellular contexts. Recently, there is increasing evidence suggesting that MALT1 might represent a novel key player in mucosal inflammation. However, the molecular mechanisms underlying this process and the targeted cell population remain unclear. In this study, we investigate the role of MALT1 proteolytic activity in the context of mucosal inflammation. We demonstrate a significant enrichment of MALT1 gene and protein expression in colonic epithelial cells of UC patients, as well as in the context of experimental colitis. Mechanistically we demonstrate that MALT1 protease function inhibits ferroptosis, a form of iron-dependent cell death, upstream of NF-κB signaling, which can promote inflammation and tissue damage in IBD. We further show that MALT1 activity contributes to STAT3 signaling, which is essential for the regeneration of the intestinal epithelium after injury. In summary, our data strongly suggests that the protease function of MALT1 plays a critical role in the regulation of immune and inflammatory responses, as well as mucosal healing. Understanding the mechanisms by which MALT1 protease function regulates these processes may offer novel therapeutic targets for the treatment of IBD and other inflammatory diseases.


Asunto(s)
Enfermedades Inflamatorias del Intestino , Transducción de Señal , Humanos , Inflamación , Enfermedades Inflamatorias del Intestino/genética , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/genética , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/metabolismo , FN-kappa B/metabolismo , Proteolisis , Células Epiteliales
18.
Eur J Immunol ; 53(2): e2250059, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36458588

RESUMEN

Toll-like receptors (TLR) control the activation of dendritic cells that prime CD4+ T cells in draining lymph nodes, where these T cells then undergo massive clonal expansion. The mechanisms controlling this clonal T cell expansion are poorly defined. Using the CD4+ T cell-mediated disease experimental autoimmune encephalomyelitis (EAE), we show here that this process is markedly suppressed when TLR9 signaling is increased, without noticeably affecting the transcriptome of primed T cells, indicating a purely quantitative effect on CD4+ T cell expansion. Addressing the underpinning mechanisms revealed that CD4+ T cell expansion was preceded and depended on the accumulation of neutrophils in lymph nodes a few days after immunization. Underlying the importance of this immune regulation pathway, blocking neutrophil accumulation in lymph nodes by treating mice with a TLR9 agonist inhibited EAE progression in mice with defects in regulatory T cells or regulatory B cells, which otherwise developed a severe chronic disease. Collectively, this study demonstrates the key role of neutrophils in the quantitative regulation of antigen-specific CD4+ T cell expansion in lymph nodes, and the counter-regulatory role of TLR signaling in this process.


Asunto(s)
Encefalomielitis Autoinmune Experimental , Ratones , Animales , Neutrófilos/patología , Receptor Toll-Like 9/metabolismo , Linfocitos T CD4-Positivos , Ganglios Linfáticos , Receptores Toll-Like/metabolismo , Ratones Endogámicos C57BL
19.
BMC Prim Care ; 23(1): 334, 2022 12 22.
Artículo en Inglés | MEDLINE | ID: mdl-36550482

RESUMEN

BACKGROUND: Though evidence on the detrimental impact of the COVID-19 pandemic in nursing homes is vast, research focusing on general practitioners' (GP) care during the pandemic in nursing homes is still scarce. METHODS: A retrospective online survey among 1,010 nursing home managers in Germany was conducted during the first wave of the COVID-19 pandemic between November 2020 and February 2021. Associations between perceived deficits in GP care (routine and acute visits) and both general and COVID-19-related characteristics of nursing homes were analysed using multiple logistic regression analyses. RESULTS: The majority of nursing home managers reported no deficits in GP care (routine visits, 84.3%; acute visits, 92.9%). Logistic regression analyses revealed that deficits in GP care (routine visits) were significantly associated with visiting restrictions for GPs and nursing home size. Small nursing homes (1-50 residents) were significantly more likely to report deficits in GP care (routine visits) compared to medium (51-100 residents) and large nursing homes (> 100 residents). Further, deficits in GP care (acute visits) were significantly associated with dementia as a focus of care and the burden of insufficient testing for SARS-CoV-2 among residents. Moreover, visiting restrictions for GPs were significantly associated with dementia as the focus of care and the COVID-19 incidence at the federal state level. Finally, COVID-19 cases in nursing homes were significantly associated with size of nursing homes, COVID-19-incidence on the federal state level and the burden of insufficient testing capacities for SARS-CoV-2 among residents. CONCLUSION: We found structural factors associated with GP care deficits during the pandemic. New concepts for GP care should be implemented in pandemic preparedness plans to ensure high quality, consistent, and reliable GP care as well as effective infection prevention measures in nursing homes.


Asunto(s)
COVID-19 , Demencia , Médicos Generales , Humanos , COVID-19/epidemiología , Pandemias/prevención & control , Estudios Retrospectivos , SARS-CoV-2 , Casas de Salud , Alemania/epidemiología
20.
Nature ; 611(7937): 794-800, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-36323785

RESUMEN

Protective immunity relies on the interplay of innate and adaptive immune cells with complementary and redundant functions. Innate lymphoid cells (ILCs) have recently emerged as tissue-resident, innate mirror images of the T cell system, with which they share lineage-specifying transcription factors and effector machinery1. Located at barrier surfaces, ILCs are among the first responders against invading pathogens and thus could potentially determine the outcome of the immune response2. However, so far it has not been possible to dissect the unique contributions of ILCs to protective immunity owing to limitations in specific targeting of ILC subsets. Thus, all of the available data have been generated either in mice lacking the adaptive immune system or with tools that also affect other immune cell subsets. In addition, it has been proposed that ILCs might be dispensable for a proper immune response because other immune cells could compensate for their absence3-7. Here we report the generation of a mouse model based on the neuromedin U receptor 1 (Nmur1) promoter as a driver for simultaneous expression of Cre recombinase and green fluorescent protein, which enables gene targeting in group 2 ILCs (ILC2s) without affecting other innate and adaptive immune cells. Using Cre-mediated gene deletion of Id2 and Gata3 in Nmur1-expressing cells, we generated mice with a selective and specific deficiency in ILC2s. ILC2-deficient mice have decreased eosinophil counts at steady state and are unable to recruit eosinophils to the airways in models of allergic asthma. Further, ILC2-deficient mice do not mount an appropriate immune and epithelial type 2 response, resulting in a profound defect in worm expulsion and a non-protective type 3 immune response. In total, our data establish non-redundant functions for ILC2s in the presence of adaptive immune cells at steady state and during disease and argue for a multilayered organization of the immune system on the basis of a spatiotemporal division of labour.


Asunto(s)
Sistema Inmunológico , Inmunidad Innata , Linfocitos , Animales , Ratones , Asma/genética , Asma/inmunología , Asma/patología , Modelos Animales de Enfermedad , Eosinófilos/patología , Inmunidad Innata/inmunología , Linfocitos/clasificación , Linfocitos/inmunología , Proteínas Fluorescentes Verdes , Sistema Inmunológico/citología , Sistema Inmunológico/inmunología , Sistema Inmunológico/patología
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