Attenuation of NF-κB in Intestinal Epithelial Cells Is Sufficient to Mitigate the Bone Loss Comorbidity of Experimental Mouse Colitis
Attenuation of NF-κB in Intestinal Epithelial Cells Is Sufficient to Mitigate the Bone Loss Comorbidity of Experimental Mouse Colitis
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DOI：
10.1002/jbmr.3759
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发表时间：
2019-10-01
影响因子：
6.2
通讯作者：
Abu-Amer, Yousef
中科院分区：
文献类型：
--
作者：
Ke, Ke;Chen, Tim (Hung-Po);Abu-Amer, Yousef
骨骼异常是炎症性肠病（IBD）的常见合并症。患有IBD的患者，包括溃疡性结肠炎和克罗恩病，都有骨骼并发症。然而，ibd相关骨质流失的机制仍然不清楚。肠道炎症在肠上皮产生炎症环境，通过肠道固有淋巴样细胞（ILCs）和其他细胞类型导致粘膜免疫失调。ilc是最近发现的被认为是肠道免疫守门人的粘膜细胞，其功能受肠上皮细胞（IEC）分泌的细胞因子调节，以响应炎症微环境。我们首先证明了从葡聚糖硫酸钠（DSS）诱导的结肠炎小鼠的肠道中收集的血清和iec含有高水平的炎症和破骨细胞因子。从机制上讲，IECs炎症反应的增强与IECs中nf - κ B（活化B细胞的核因子κ轻链增强子）的显著内在活化以及ILC1、ILC3和髓系破骨细胞祖细胞频率的增加有关。为了验证iec特异性NF-kappa B激活在这一现象中的核心作用，小鼠iec中组成活性抑制剂kappa B激酶2 （IKK2）的条件表达概括了化学诱导结肠炎中观察到的大多数细胞、炎症和溶骨表型。此外，IECs中IKK2的条件缺失显著减轻了dss诱导结肠炎的炎症和骨质流失。最后，在dss诱导的结肠炎模型中，药理抑制IKK2可有效降低ILC1和ILC3细胞的频率，降低炎症细胞因子的循环水平，并阻止结肠炎相关的骨质流失。我们的研究结果确定IECs中的IKK2是结肠炎相关骨质减少的可行治疗靶点。
Skeletal abnormalities are common comorbidities of inflammatory bowel disease (IBD). Patients suffering from IBD, including ulcerative colitis and Crohn's disease, present with skeletal complications. However, the mechanism underpinning IBD-associated bone loss remains vague. Intestinal inflammation generates an inflammatory milieu at the intestinal epithelium that leads to dysregulation of mucosal immunity through gut-residing innate lymphoid cells (ILCs) and other cell types. ILCs are recently identified mucosal cells considered as the gatekeeper of gut immunity and their function is regulated by intestinal epithelial cell (IEC)-secreted cytokines in response to the inflammatory microenvironment. We first demonstrate that serum as well as IECs collected from the intestine of dextran sulfate sodium (DSS)-induced colitis mice contain high levels of inflammatory and osteoclastogenic cytokines. Mechanistically, heightened inflammatory response of IECs was associated with significant intrinsic activation of NF-kappa B (nuclear factor kappa-light-chain-enhancer of activated B cells) in IECs and increased frequency of ILC1, ILC3, and myeloid osteoclast progenitors. Validating the central role of IEC-specific NF-kappa B activation in this phenomenon, conditional expression of constitutively active inhibitor kappa B kinase 2 (IKK2) in IECs in mice recapitulates the majority of the cellular, inflammatory, and osteolytic phenotypes observed in the chemically induced colitis. Furthermore, conditional deletion of IKK2 from IECs significantly attenuated inflammation and bone loss in DSS-induced colitis. Finally, using the DSS-induced colitis model, pharmacologic inhibition of IKK2 was effective in reducing frequency of ILC1 and ILC3 cells, attenuated circulating levels of inflammatory cytokines, and halted colitis-associated bone loss. Our findings identify IKK2 in IECs as viable therapeutic target for colitis-associated osteopenia.