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MUC1 Mitigates Renal Injury and Inflammation in Endotoxin-Induced Acute Kidney Injury by Inhibiting the TLR4-MD2 Axis and Reducing Pro-inflammatory Macrophages Infiltration

Abstract : 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 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 MUC1 cytosolic domain (CT) seems necessary for the negative regulation of TLR4 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.
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https://hal.archives-ouvertes.fr/hal-03379151
Contributor : Isabelle van Seuningen Connect in order to contact the contributor
Submitted on : Thursday, October 14, 2021 - 10:21:09 PM
Last modification on : Friday, November 5, 2021 - 3:55:12 PM

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Jean-Baptiste Gibier, Thomas Swierczewski, Marie Csanyi, Brigitte Hemon, Francois Glowacki, et al.. MUC1 Mitigates Renal Injury and Inflammation in Endotoxin-Induced Acute Kidney Injury by Inhibiting the TLR4-MD2 Axis and Reducing Pro-inflammatory Macrophages Infiltration. Shock, Lippincott, Williams & Wilkins, 2021, 56 (4), pp.629-638. ⟨10.1097/SHK.0000000000001742⟩. ⟨hal-03379151⟩

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