Background & Aims: Junctional adhesion molecule-A (JAM-A) is localized at the tight junctions and controls leukocyte migration into the tissues. However, its functional role in inflammatory bowel ...disease (IBD) is unexplored. Methods: Control, Crohn's disease (CD), and ulcerative colitis (UC) tissue specimens were studied for JAM-A expression, as well as the colon of mice given dextran sodium sulfate (DSS). Wild-type and JAM-A-/- , Tie-2-Cre-JAM-A-/- (endothelial/hematopoietic-specific JAM inactivation) mice were studied for susceptibility to DSS. Disease activity and colonic inflammation were assessed using a disease activity index histology and endoscopy, and mucosal cytokines were measured by enzyme-linked immunosorbent assay. JAM-A function was investigated by RNA silencing in epithelial cells, and apoptosis was measured. Results: In both CD and UC, as well as in experimental colitis, there is a loss of epithelial but not endothelial JAM-A expression. Deletion of JAM-A results in a dramatic increase in susceptibility to DSS colitis, as assessed by weight loss, disease activity index, histologic and endoscopic severity, and strikingly high mortality rates. This is not caused by the absence of JAM-A in the endothelial or hematopoietic compartments because Tie-2-Cre–JAM-A-/- mice are no more susceptible to DSS colitis than wild-type animals. JAM-A-/- mice displayed increased intestinal permeability and inflammatory cytokine production, and marked epithelial apoptosis. Silencing of JAM-A in intestinal epithelial cells resulted in increased permeability in vitro. Conclusions: Our results show a nonredundant and novel role of JAM-A in controlling mucosal homeostasis by regulating the integrity and permeability of epithelial barrier function.
Colorectal cancer (CRC) is one of the most malignant tumors worldwide. Stromal cells residing in the tumor microenvironment strongly contribute to cancer progression through their crosstalk with ...cancer cells and extracellular matrix. Here we provide the first evidence that CRC‐associated lymphatic endothelium displays a distinct matrisome‐associated transcriptomic signature, which distinguishes them from healthy intestinal lymphatics. We also demonstrate that CRC‐associated human intestinal lymphatic endothelial cells regulate tumor cell growth via growth differentiation factor 11, a soluble matrisome component which in CRC patients was found to be associated with tumor progression. Our data provide new insights into lymphatic contribution to CRC growth, aside from their conventional role as conduits of metastasis.
What's new?
Stromal cells residing in the tumor microenvironment strongly contribute to tumor progression through their crosstalk with cancer cells and extracellular matrix (ECM). In this study, the authors demonstrate that colorectal cancer (CRC)‐associated human intestinal lymphatic endothelial cells (HILEC) regulate tumor cell growth via the soluble matrisome component Growth Differentiation Factor 11 (GDF11), pointing to an unconventional role of lymphatics in controlling CRC growth and progression aside from their classical role as conduit of metastasis. The findings pave the way for new studies ultimately aiming at the identification of GDF11 inhibitors for the treatment of CRC in its early phases.
The purpose of this study was to present data on the safety of anti- severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in a cohort of inflammatory bowel disease (IBD) patients ...of an ongoing multicenter study (ESCAPE-IBD) sponsored by the Italian Group for the study of Inflammatory Bowel Disease (ClinicalTrials.gov Identifier: NCT04769258).
Anti-SARS-CoV-2 vaccination was administrated to 809 IBD patients. Interviews were conducted to report adverse events related to vaccination. Of these 809, 346 patients were surveyed on the pandemic burden and the main reason for hesitancy in coronavirus disease 2019 vaccination. The chi-square test was used to compare categorical variables. Logistic regression was used to assess the relationship between disease-related characteristics and the onset of adverse events.
About 45% of patients had at least one side effect, following the first dose (10%), the second (15%), and both doses (19%). All the adverse events were mild and lasted only a few days. Logistic regression analysis revealed that female sex ( P < 0.001), younger age ( P = 0.001), seroconversion ( P = 0.002), and comorbidity ( P < 0.001) were significantly associated with adverse events. The survey showed that the main concerns were the possibility of adverse event (33%). Almost all patients (99%) felt safer having been vaccinated at their IBD reference center.
The vaccine reactions experienced in IBD patients were mostly self-limited. We found high acceptance and good safety of SARS-CoV-2 vaccination in our cohort.
Inflammation plays crucial roles in the pathogenesis of several chronic inflammatory disorders, including Crohn's disease (CD) and UC, the two major forms of IBD. The urokinase plasminogen activator ...receptor (uPAR) exerts pleiotropic functions over the course of both physiological and pathological processes. uPAR not only has a key role in fibrinolysis but also modulates the development of protective immunity. Additionally, uPAR supports extracellular matrix degradation and regulates cell migration, adhesion and proliferation, thus influencing the development of inflammatory and immune responses. This study aimed to evaluate the role of uPAR in the pathogenesis of IBD.
The functional role of uPAR was assessed in established experimental models of colitis. uPAR deficiency effects on cytokine release, polarisation and bacterial phagocytosis were analysed in colonic macrophages. uPAR expression was analysed in surgical specimens collected from normal subjects and patients with IBD.
In mice, uPAR expression is positively regulated as colitis progresses. uPAR-KO mice displayed severe inflammation compared with wild-type littermates, as indicated by clinical assessment, endoscopy and colon histology. The absence of uPAR led to an increased production of inflammatory cytokines by macrophages that showed an M1 polarisation and impaired phagocytosis. In human IBD, CD68(+) macrophages derived from the inflamed mucosa expressed low levels of uPAR.
These findings point to uPAR as an essential component of intestinal macrophage functions and unravel a new potential target to control mucosal inflammation in IBD.
Although tumor-associated macrophages (TAM) display a M2-skewed tumor-promoting phenotype in most cancers, in colorectal cancer, both TAM polarization and its impact remain controversial. We ...investigated the role of the M2-polarizing p50 NF-κB subunit in orchestrating TAM phenotype, tumor microenvironment composition, and colorectal cancer progression. We first demonstrated, by parallel studies in colitis-associated cancer (CAC) and in genetically driven Apc
mouse models, that the p50-dependent inhibition of M1-polarized gut inflammation supported colorectal cancer development. In accordance with these studies, p50
mice displayed exacerbated CAC with fewer and smaller tumors, along with enhanced levels of M1/Th1 cytokines/chemokines, including IL12 and CXCL10, whose administration restrained CAC development
The inflammatory profile supporting tumor resistance in colons from p50
tumor bearers correlated inversely with TAM load and positively with both recruitment of NK, NKT, CD8
T cells and number of apoptotic tumor cells. In agreement, myeloid-specific ablation of p50 promoted tumor resistance in mice, whereas in colorectal cancer patients, a high number of p50
TAMs at the invasive margin was associated with decreased
and
expression and worse postsurgical outcome. Our findings point to p50 involvement in colorectal cancer development, through its engagement in the protumor activation of macrophages, and identify a candidate for prognostic and target therapeutic intervention.
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Introduction: Adaptive immunity in intestinal inflammation may play a key role in the pathogenesis of Crohn's disease. In particular, interleukin (IL)-23 may be a key mediator in chronic intestinal ...inflammation by inducing the differentiation of naïve CD4 + T cells into Th17, with the production of several pro-inflammatory cytokines. Furthermore, IL-23 induces interferon-γ (IFN- γ) production from activated T cells, a critical cytokine in innate and adaptive immunity against infections.
Areas covered: We aim to review the available data from literature regarding the role of IL-23, with a more specific focus on the recent progresses in the therapeutic modulation of this cytokine.
Expert commentary: Increased knowledge regarding the role of IL-23 has allowed for the development of effective therapeutic progresses by blocking the IL-23 mediated pathways. Primary or secondary loss of response to anti-TNF therapies in Crohn's disease patients during the first year is widely described in literature: the development of new drugs, with alternative mechanisms of action, is thus a key point to consider for the optimal management of these subjects. Drugs blocking the IL-12/23 pathway showed a good efficacy and safety profile in immune-mediated diseases Further studies are necessary regarding the role of the single blockade of IL-23.
Patients on immunosuppressive drugs have been excluded from COVID-19 vaccines trials, creating concerns regarding their efficacy.
To explore the humoral response to COVID-19 vaccines in patients with ...inflammatory bowel disease (IBD)
Effectiveness and Safety of COVID-19 Vaccine in Patients with Inflammatory Bowel Disease (IBD) Treated with Immunomodulatory or Biological Drugs (ESCAPE-IBD) is a prospective, multicentre study promoted by the Italian Group for the study of Inflammatory Bowel Disease. We present data on serological response eight weeks after the second dose of COVID-19 vaccination in IBD patients and healthy controls (HCs).
1076 patients with IBD and 1126 HCs were analyzed. Seropositivity for anti-SARS-CoV-2 IgG was reported for most IBD patients, even if with a lesser rate compared with HCs (92.1% vs. 97.9%; p<0.001). HCs had higher antibody concentrations (median OD 8.72 IQR 5.2-14-2) compared to the whole cohort of IBD patients (median OD 1.54 IQR 0.8-3.6; p<0.001) and the subgroup of IBD patients (n=280) without any treatment or on aminosalicylates only (median OD 1.72 IQR 1.0–4.1; p<0.001).
Although most IBD patients showed seropositivity after COVID-19 vaccines, the magnitude of the humoral response was significantly lower than in HCs. Differently from other studies, these findings seem to be mostly unrelated to the use of immune-modifying treatments (ClinicalTrials.govID:NCT04769258).
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