Search

Schistosoma mansoni eggs retained in host tissues induce innate cytokine release, contributing to the induction of Type-2 immune responses and granuloma formation, important to restrain cytotoxic antigens, but leading to fibrosis. Interleukin(IL)-33 participates in experimental models of inflammation and chemically induced fibrosis, but its role in S. mansoni-induced fibrosis is still unknown. To explore the role of the IL-33/suppressor of the tumorigenicity 2 (ST2) pathway, serum and liver cytokine levels, liver histopathology, and collagen deposition were comparatively evaluated in S. mansoni-infected wild-type (WT) and IL-33-receptor knockout (ST2−/−) BALB/c mice. Our data show similar egg counts and hydroxyproline in the livers of infected WT and ST2−/− mice; however, the extracellular matrix in ST2−/− granulomas was loose and disorganised. Pro-fibrotic cytokines, such as IL-13 and IL-17, and the tissue-repairing IL-22 were significantly lower in ST2−/− mice, especially in chronic schistosomiasis. ST2−/− mice also showed decreased α-smooth muscle actin (α-SMA) expression in granuloma cells, in addition to reduced Col III and Col VI mRNA levels and reticular fibres. Therefore, IL-33/ST2 signalling is essential for tissue repairing and myofibroblast activation during S. mansoni infection. Its disruption results in inappropriate granuloma organisation, partly due to the reduced type III and VI collagen and reticular fibre formation. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite the clinical benefit of new anticancer therapies, such as immune checkpoint inhibitors, lung cancer remains the most frequent cause of cancer-related death worldwide, thus supporting the need to develop novel anticancer treatments. Endothelial cells of the tumor-associated vasculature are easily accessible to drugs administered intravenously, besides having greater genetic stability than neoplastic cells and thus lowering the risk of developing drug resistance. In this respect, the identification of alternative targets, and therapeutic strategies, within the tumor vasculature is of high relevance. Accordingly, this work aimed at characterizing nucleolin expression in patient-derived pulmonary carcinomas and further validating nucleolin as a novel target to mediate successful therapeutic interventions against human lung cancers. The highlighted prognostic value of nucleolin points towards the applicability of nucleolin-based targeting strategies against nucleolinhigh pulmonary carcinomas, present in every disease stage, in a clinical trial setting. Notwithstanding the advances in the treatment of lung cancer with immune checkpoint inhibitors, the high percentage of non-responders supports the development of novel anticancer treatments. Herein, the expression of the onco-target nucleolin in patient-derived pulmonary carcinomas was characterized, along with the assessment of its potential as a therapeutic target. The clinical prognostic value of nucleolin for human pulmonary carcinomas was evaluated through data mining from the Cancer Genome Atlas project and immunohistochemical detection in human samples. Cell surface expression of nucleolin was evaluated by flow cytometry and subcellular fraction Western blotting in lung cancer cell lines. Nucleolin mRNA overexpression correlated with poor overall survival of lung adenocarcinoma cancer patients and further predicted the disease progression of both lung adenocarcinoma and squamous carcinoma. Furthermore, a third of the cases presented extra-nuclear expression, contrasting with the nucleolar pattern in non-malignant tissues. A two- to twelve-fold improvement in cytotoxicity, subsequent to internalization into the lung cancer cell lines of doxorubicin-loaded liposomes functionalized by the nucleolin-binding F3 peptide, was correlated with the nucleolin cell surface levels and the corresponding extent of cell binding. Overall, the results suggested nucleolin overexpression as a poor prognosis predictor and thus a target for therapeutic intervention in lung cancer. [ABSTRACT FROM AUTHOR]

Background: Increasing evidence supports a key role for inflammation in the neurodegenerative process of familial amyloidotic polyneuropathy (FAP). While there seems to be an overactivation of the neuronal interleukin-1 signaling pathway, the immune response is apparently compromised in FAP. Accordingly, little immune cell infiltration is observed around pre-fibrillar or fibrillar amyloid deposits, with the underlying mechanism for this phenomenon remaining poorly understood. Cathepsin E (CtsE) is an important intermediate for antigen presentation and chemotaxis, but its role in the pathogenesis of FAP disease remains unknown.Methods: In this study, we used both mouse primary macrophages and in vivo studies based on transgenic models of FAP and human samples to characterize CtsE expression in different physiological systems.Results: We show that CtsE is critically decreased in bone marrow-derived macrophages from a FAP mouse model, possibly contributing for cell function impairment. Compromised levels of CtsE were also found in injured nerves of transgenic mice and, most importantly, in naïve peripheral nerves, sensory ganglia, murine stomach, and sural nerve biopsies derived from FAP patients. Expression of CtsE in tissues was associated with transthyretin (TTR) deposition and differentially regulated accordingly with the physiological system under study. Preventing deposition with a TTR small interfering RNA rescued CtsE in the peripheral nervous system (PNS). In contrast, the expression of CtsE increased in splenic cells (mainly monocytes) or peritoneal macrophages, indicating a differential macrophage phenotype.Conclusion: Altogether, our data highlights the potential of CtsE as a novel FAP biomarker and a possible modulator for innate immune cell chemotaxis to the disease most affected tissues-the peripheral nerve and the gastrointestinal tract. [ABSTRACT FROM AUTHOR]

• Strongyloides Strongyloides co-infection in mice did not alter the schistosome parasite burden. • Co-infection resulted in earlier induction of modulatory response. • Simultaneous co-infection stimulated IFN-γ output, increased inflammation and injury. • Co-infection at acute schistosomiasis intensified Th1/Th2/Th17 response and inflammation. • Co-infection alters immune response and liver inflammation induced by schistosomiasis. Human co-infection by helminth species is frequent, but their consequences are mostly unknown. Here, we investigate the impact of Strongyloides venezuelensis co-infection on the immune response, schistosome burden, and the associated pathology of schistosomiasis in mice. Co-infection did not alter the schistosome parasite burden, but reduced the IL-4/IL-10 ratio during acute schistosomiasis, indicating induction of modulatory mechanisms. Simultaneous infection with S. venezuelensis and S. mansoni increased the liver concentration of IFN-γ and altered the Th2/Th1 balance, leading to great infiltration of neutrophils and macrophages, which resulted in larger liver inflammation and increased serum transaminase activity in comparison with mono-infected mice. Mice infected with S. venezuelensis at two and four weeks after S. mansoni infection showed significant increase of Th1/Th2/Th17/Treg cytokines and strong cellular infiltration in the liver in comparison with mono-infected mice. However, only in mice co-infected after two weeks of schistosomiasis, the liver immune response leads to more intense Th2 polarization, increased liver inflammation, and transaminase serum activity. S. venezuelensis co-infection during chronic schistosomiasis did not significantly alter liver inflammation. Therefore, S. venezuelensis co-infection affects the host immune responses and morbidity of schistosomiasis, but the effects largely depend on the stage of the S. mansoni infection. [ABSTRACT FROM AUTHOR]