Biology subjects

Nava, P.

Publications and source records attributed to Nava, P..

4 recordsLinked to original sources

bioRxiv2023

Paneth and Paneth-like cells undergoing necroptosis fuel intestinal epithelial cell proliferation following IFN-γ stimulation.

The quality of life in patients with inflammatory bowel diseases (IBD) is strongly impaired. Alterations of intestinal epithelial homeostasis contribute to the development and establishment of IBD. Intestinal Paneth and Paneth-like cells produce and secrete luminal proteins sustaining epithelial homeostasis. Here we show that IFN-{gamma} stimulates Paneth and Paneth-like cells degranulation that triggers the proliferation of intestinal epithelial cells (IEC) in a Wnt/{beta}-catenin independent manner. Degranulation in Paneth and Paneth-like cells was mTORC1 and necroptosis dependent. Remarkably, lack of IFN-{gamma}, inhibition of mTORC1, or impeding necroptosis reduces IEC proliferation cytokine-mediated. Our findings identify a new role for IFN-{gamma} in stimulating IEC proliferation through inducing degranulation of Paneth and Paneth-like cells which is mTORC1 and necroptosis- dependent. In a mouse model of colitis, mTORC1 activation and necroptosis regulate Paneth and Paneth-like cell secretion. Furthermore, the colitogenic environment triggers PC metaplasia in the distal region of the large intestine to simulate cell proliferation. HighlightsIFN-{gamma} stimulates proliferation, {beta}-catenin independent. IFN-{gamma} enhances mitochondrial activity and proliferation IFN-{gamma} regulates PC biogenesis. mTORC1-dependent necroptosis mediates secretion in Paneth and Paneth-like cells.

physiology↗

bioRxiv2023

Exposure to an enriched environment improves colonic epithelial barrier integrity and attenuates mouse experimental colitis by modulating a Myc-driven gene regulatory network

Withdrawal StatementThe authors have withdrawn their manuscript owing to erroneous labeling in two figures that have recently come to light. Experiments aiming to confirm the data presented are underway. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

immunology↗

bioRxiv2023

Cytotrophoblast cells are selectively permissive and favor Zika virus, but no other related flavivirus, invasion to the placental stroma

BACKGROUNDZika virus (ZIKV) is highly teratogenic, in contrast with dengue virus (DENV) or the yellow fever virus vaccine (YFV-17D). The mechanisms employed by ZIKV to cross the placenta need to be elucidated. METHODSParallel infections with ZIKV, DENV and YFV-17D were compared in terms of efficiency, activation of mTOR pathways and cytokine secretion profile in human cytotrophoblastic HTR8 cells (CTB), and monocytic U937 cells, differentiated to M2 macrophages (M2-MO). RESULTSIn CTB, ZIKV replication was significantly more efficient than DENV or YFV-17D. In M2-MO, ZIKV replication continued to be more efficient, although differences between strains were reduced. Significantly greater activation of Phospho-S6r and Phospho-AKT/Ser473 fractions in CTB infected with ZIKV than with DENV or YFV-17D, was observed. CTB treated with the mTOR inhibitors rapamycin or AZD8055, showed a 20-fold-reduction in ZIKV yield, versus 5 and 3.5-fold for DENV and YFV-17D, respectively. Finally, we detected that ZIKV infection, but not DENV or YFV-17D, efficiently inhibited the interferon response of CTB cells. CONCLUSIONSThese results suggest that CTB cells are permissive and act favoring ZIKV entry into the placental stroma, over DENV and YFV-17D and that the mTOR complex is a switch that enhances the replication of ZIKV in CTB cells.

microbiology↗

bioRxiv2021

ADAM17 inhibition prevents neutrophilia and lung injury in a mouse model of Covid-19

Severe coronavirus disease 2019 (Covid-19) is characterized by lung injury, cytokine storm and increased neutrophil-to-lymphocyte ratio (NLR). Current therapies focus on reducing viral replication and inflammatory responses, but no specific treatment exists to prevent the development of severe Covid-19 in infected individuals. Angiotensin-converting enzyme-2 ACE-2) is the receptor for SARS-CoV-2, the virus causing Covid-19, but it is also critical for maintaining the correct functionality of lung epithelium and endothelium. Coronaviruses induce activation of a disintegrin and metalloprotease 17 (ADAM17) and shedding of ACE-2 from the cell surface resulting in exacerbated inflammatory responses. Thus, we hypothesized that ADAM17 inhibition ameliorates Covid-19-related lung inflammation. We employed a pre-clinical mouse model using intra-tracheal instillation of a combination of polyinosinic:polycytidylic acid (poly-I:C) and the receptor-binding domain of the SARS-CoV-2 spike protein (RBD-S) to mimic lung damage associated with Covid-19. Histological analysis of inflamed mice confirmed the expected signs of lung injury including edema, fibrosis, vascular congestion and leukocyte infiltration. Moreover, inflamed mice also showed an increased NLR as observed in critically ill Covid-19 patients. Administration of the ADAM17 inhibitors apratastat and TMI-1 significantly improved lung histology and prevented leukocyte infiltration. Reduced leukocyte recruitment could be explained by reduced production of pro-inflammatory cytokines and lower levels of the endothelial adhesion molecules ICAM-1 and VCAM-1. Additionally, the NLR was significantly reduced by ADAM17 inhibition. Thus, we propose inhibition of ADAM17 as a novel promising treatment strategy in SARS-CoV-2-infected individuals to prevent the progression towards severe Covid-19.

pathology↗