MUC1 Mitigates Renal Injury and Inflammation in Endotoxin-Induced Acute Kidney Injury by Inhibiting the TLR4-MD2 Axis and Reducing Pro-inflammatory Macrophages Infiltration
| Autor: | Jean-Baptiste Gibier, Isabelle Van Seuningen, Thomas Swierczewski, Patrice Maboudou, Nicolas Pottier, Sébastien Aubert, Brigitte Hémon, François Glowacki, Michael Perrais, Marie Csanyi, Christelle Cauffiez, Viviane Gnemmi |
|---|---|
| Přispěvatelé: | Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Service de pathologie [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de Néphrologie et Transplantation rénale [CHRU-lille] |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
Lipopolysaccharide [SDV]Life Sciences [q-bio] Lymphocyte Antigen 96 Inflammation Critical Care and Intensive Care Medicine digestive system Proinflammatory cytokine Sepsis Mice chemistry.chemical_compound medicine Animals Receptor skin and connective tissue diseases neoplasms business.industry Macrophages Mucin-1 Mucin Acute kidney injury Acute Kidney Injury medicine.disease biological factors digestive system diseases 3. Good health Endotoxins Mice Inbred C57BL Toll-Like Receptor 4 chemistry Emergency Medicine Cancer research TLR4 Female medicine.symptom business |
| Zdroj: | Shock Shock, Lippincott, Williams & Wilkins, 2021, 56 (4), pp.629-638. ⟨10.1097/SHK.0000000000001742⟩ Shock, 2021, 56 (4), pp.629-638. ⟨10.1097/SHK.0000000000001742⟩ |
| ISSN: | 1073-2322 |
| DOI: | 10.1097/SHK.0000000000001742⟩ |
| Popis: | Sepsis is the leading cause of acute kidney injury (AKI) in critical care patients. A cornerstone of sepsis-associated AKI is dysregulated inflammation driven by excessive activation of Toll-like receptor 4 (TLR4) pathway. MUC1, a membrane bound mucin expressed in both epithelial tubular cells and renal macrophages, has been shown to be involved in the regulation of TLRs. Therefore we hypothesized that MUC1 could mitigate the renal inflammatory response to TLR4 activation. To test this hypothesis, we used a murine model of endotoxin-induced AKI by intraperitoneal injection of lipopolysaccharide (LPS). We showed that Muc1-/- mice have a more severe renal dysfunction, an increased activation of the tissular NF-kB pathway and secreted more pro inflammatory cytokines compare to Muc1+/+ mice. By flow cytometry, we observed that the proportion of M1 (pro-inflammatory) macrophages in the kidneys of Muc1-/- mice was significantly increased. In human and murine primary macrophages, we showed that MUC1 is only induced in M1 type macrophages and that macrophages derived from Muc1-/- mice secreted more pro-inflammatory cytokines. Eventually, in HEK293 cells, we showed that (i) MUC1 cytosolic domain (CT) seems necessary for the negative regulation of TLR4 (ii) by proximity ligation assay, MUC1-CT is in close relationship with TLR4 and acts as a competitive inhibitor of the recruitment of MYD88. Overall our results support that in the context of endotoxin-induced AKI, MUC1 plays a significant role in controlling disease severity by regulating negatively the TLR4-MD2 axis. |
| Databáze: | OpenAIRE |
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