Macrophage MerTK promotes profibrogenic cross-talk with hepatic stellate cells via soluble mediators

Background & Aims: Activation of Kupffer cells and recruitment of monocytes are key events in fibrogenesis. These cells release soluble mediators which induce the activation of hepatic stellate cells (HSCs), the main fibrogenic cell type within the liver. Mer tyrosine kinase (MerTK) signaling regulates multiple processes in macrophages and has been implicated in the pathogenesis of non-alcoholic steatohepatitis-related fibrosis. In this study, we explored if MerTK activation in macrophages influences the profibrogenic phenotype of HSCs. Methods: Macrophages were derived from THP-1 cells or differentiated from peripheral blood monocytes towards MerTK+/CD206+/CD163+/CD209- macrophages. The role of MerTK was assessed by pharmacologic and genetic inhibition. HSC migration was determined in Boyden chambers, viability was measured by the MTT assay, and proliferation was evaluated by the BrdU incorporation assay. Results: Gas-6 induced MerTK phosphorylation and Akt activation in macrophages, and these effects were inhibited by UNC569. During polarization, MerTK+/CD206+/CD163+/CD209- macrophages exhibited activation of STAT3, ERK1/2, p38 and increased expression of VEGF-A. Activation of MerTK in THP-1 macrophages induced a secretome which promoted a significant increase in migration, proliferation, viability and expression of profibrogenic factors in HSCs. Similarly, conditioned medium from MerTK+ macrophages induced a significant increase in cell migration, proliferation, STAT3 and p38 phosphorylation and upregulation of IL-8 expression in HSCs. Moreover, conditioned medium from Gas-6-stimulated Kupffer cells induced a significant increase in HSC proliferation. These effects were specifically related to MerTK expression and activity in macrophages, as indicated by pharmacologic inhibition and knockdown experiments. Conclusions: MerTK activation in macrophages modifies the secretome to promote profibrogenic features in HSCs, implicating this receptor in the pathogenesis of hepatic fibrosis. Lay summary: Fibrosis represents the process of scarring occurring in patients with chronic liver diseases. This process depends on production of scar tissue components by a specific cell type, named hepatic stellate cells, and is regulated by interaction with other cells. Herein, we show that activation of MerTK, a receptor present in a population of macrophages, causes the production of factors that act on hepatic stellate cells, increasing their ability to produce scar tissue

Nidificazione della Caretta caretta e partecipazione pubblica al progresso della scienza: un esempio di citizen science

L’evento della nidificazione di una Caretta Caretta nel sito più a nord del Mediterraneo finora registrato, ovvero presso la spiaggia di Santa Lucia di Castiglioncello, ha rappresentato per la Toscana un vero e proprio evento scientifico pubblico, probabilmente il più seguito dell’estate 2018 dai cittadini di tutta l’area livornese e non solo. La partecipazione pubblica a questo evento eccezionale non si è limitata ad un costante interessamento all’evolversi dell’evento, ma ha visto anche una partecipazione attiva agli aspetti scientifici legati alla nidificazione e alla raccolta di dati relativi alla nascita delle prime tartarughine di questa area. Si è trattato a tutti gli effetti di un esempio, non programmato, di Citizen Science, ovvero di partecipazione attiva dei cittadini ad un evento scientifico. In questa breve comunicazione ripercorreremo brevemente le tappe più significative di questo evento proprio dal punto di vista della partecipazione pubblica

The protein kinase CK2 contributes to the malignant phenotype of cholangiocarcinoma cells

Cholangiocarcinoma (CCA) is a particularly aggressive hepatobiliary malignancy, for which the molecular mechanisms underlying the malignant phenotype are still poorly understood, and novel and effective therapeutic strategies are limited. The pro-survival protein kinase CK2 is frequently overexpressed in cancer and is receiving increasing interest as an anti-tumor drug target. Its precise role in CCA biology is still largely unknown. Here we show that expression of the CK2\u3b1 and \u3b1' catalytic subunits and of the \u3b2 regulatory subunit is increased in human CCA samples. Increased expression of CK2 subunits was shown in CCA cell lines compared to non-transformed cholangiocytes. We used chemical inhibition of CK2 and genetic modification by CRISPR/Cas9 to explore the contribution of CK2 to the malignant phenotype of CCA cells. Disruption of CK2 activity results in cell death through apoptosis, reduced invasion and migration potential, and G0/G1 cell cycle arrest. Importantly, CCA cells with a reduced CK2 activity are more sensitive to chemotherapy. Altogether, our results demonstrate that CK2 significantly contributes to increased proliferative potential and augmented growth of CCA cells and indicate the rationale for its targeting as a promising pharmacologic strategy for cholangiocarcinoma

The protease-inhibitor serpinB3 as a critical modulator of the stem-like subset in human cholangiocarcinoma

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