Genetic Deletion of LRP5 and LRP6 in Macrophages Exacerbates Colitis-Associated Systemic Inflammation and Kidney Injury in Response to Intestinal Commensal Microbiota.
Genetic Deletion of LRP5 and LRP6 in Macrophages Exacerbates Colitis-Associated Systemic Inflammation and Kidney Injury in Response to Intestinal Commensal Microbiota.
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DOI：
10.4049/jimmunol.2101172
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发表时间：
2022-07-15
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肠外表现在炎症性肠病（IBD）中很常见，并涉及几个器官，包括肾脏。然而，IBD肾脏表现的机制尚不清楚。在这里，我们表明，在巨噬细胞中的Wnt-LRP 5/6信号通路在调节小鼠葡聚糖硫酸钠（DSS）诱导的结肠炎模型中结肠炎相关的全身炎症和肾损伤中起着关键作用。小鼠巨噬细胞中Wnt辅助受体低密度脂蛋白受体相关蛋白5和6（LRP 5/6）的条件性缺失导致对DSS-结肠炎诱导的全身炎症和急性肾损伤（阿基）的易感性增强。此外，我们的研究表明，在LRP 5/6LyzM小鼠中观察到的结肠炎相关全身性炎症和阿基加重是由于细菌移位到肠外部位的增加和肾脏中微生物群依赖性促炎细胞因子水平的增加。相反，肠道微生物群的消耗减轻了LRP 5/6LysM小鼠中结肠炎相关的全身性炎症和阿基。从机制上讲，LRP 5/6缺陷型巨噬细胞对TLR配体反应过度，并产生更高水平的促炎细胞因子，这些促炎细胞因子与MAPK活化增加相关。这些结果揭示了巨噬细胞中的Wnt-LRP 5/6信号传导如何控制结肠炎诱导的全身炎症和阿基。
Extraintestinal manifestations are common in inflammatory bowel disease (IBD) and involve several organs, including the kidney. However, the mechanisms responsible for renal manifestation in IBD are not known. Here, we show that the Wnt-LRP5/6-signaling pathway in macrophages plays a critical role in regulating colitis-associated systemic inflammation and renal injury in a murine dextran sodium sulfate (DSS)-induced colitis model. Conditional deletion of the Wnt coreceptors low-density lipoprotein receptor-related protein 5 and 6 (LRP5/6) in macrophages in mice results in enhanced susceptibility to DSS-colitis-induced systemic inflammation and acute kidney injury (AKI). Furthermore, our studies show that aggravated colitis-associated systemic inflammation and AKI observed in LRP5/6LyzM mice are due to increased bacterial translocation to extraintestinal sites and microbiota-dependent increased proinflammatory cytokine levels in the kidney. Conversely, depletion of the gut microbiota mitigated colitis-associated systemic inflammation and AKI in LRP5/6LysM mice. Mechanistically, LRP5/6-deficient macrophages were hyperresponsive to TLR ligands and produced higher levels of proinflammatory cytokines which are associated with increased activation of MAPKs. These results reveal how the Wnt-LRP5/6 signaling in macrophages controls colitis-induced systemic inflammation and AKI.
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4.6
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Cosín-Roger J;Ortiz-Masiá D;Calatayud S;Hernández C;Alvarez A;Hinojosa J;Esplugues JV;Barrachina MD
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Förster, I
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Ruiz-Ortega M