Background HMGB1 is a ubiquitous nucleoprotein with immune-regulatory properties following cellular secretion or release in sterile and infectious inflammation. Stool and serum HMGB1 levels correlate with colitis severity and colorectal cancer (CRC) progression, yet recent reports indicated HMGB1 to mainly operate as an intracellular determinant of enterocyte fate during colitis, and investigations into the roles of HMGB1 in CRC are lacking. Using mice with conditional HMGB1-knockout in enterocytes (Hmgb1ΔIEC) and myeloid cells (Hmgb1ΔLysM), respectively, we explored functions of HMGB1 in pathogenetically diverse contexts of colitis and colitis-associated CRC. Results HMGB1 is overexpressed in human inflammatory bowel disease and gastrointestinal cancers, and HMGB1 protein localizes in enterocytes and stromal cells in colitis and CRC specimens from humans and rodents. As previously described, enterocyte HMGB1 deficiency aggravates severe chemical-induced intestinal injury, but not Citrobacter rodentium or T cell transfer colitis in mice. HMGB1-deficient enterocytes and organoids do not exhibit deviant apoptotic or autophagic activity, altered proliferative or migratory capacity, abnormal intestinal permeability or aberrant DSS-induced organoid inflammation in vitro. Instead, we observed altered in vivo-reprogramming of both intestinal epithelia and infiltrating myeloid cells in Hmgb1ΔIEC early during colitis, suggesting HMGB1-mediated paracrine injury signaling. Hmgb1ΔIEC had higher CRC burden than wildtypes in the Apc+/min model, whereas inflammatory CRC was attenuated in Hmgb1ΔLysM. Cellular and molecular phenotyping of Hmgb1ΔIEC and Hmgb1ΔLysM cancers indicates context-dependent transcriptional modulation of immune signaling and extracellular matrix remodeling via HMGB1. Conclusion Enterocytes and myeloid cells context-dependently regulate host responses to severe colitis and maladaptive intestinal wound healing via HMGB1.

中文翻译：

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肠上皮和骨髓免疫细胞通过高迁移率族盒蛋白 1 影响结肠炎的严重程度和结直肠癌的发生

背景 HMGB1 是一种普遍存在的核蛋白，在无菌和感染性炎症中细胞分泌或释放后具有免疫调节特性。粪便和血清 HMGB1 水平与结肠炎严重程度和结直肠癌 (CRC) 进展相关，但最近的报告表明 HMGB1 主要作为结肠炎期间肠细胞命运的细胞内决定因素，并且缺乏对 HMGB1 在 CRC 中作用的研究。使用分别条件性敲除肠上皮细胞 (Hmgb1ΔIEC) 和骨髓细胞 (Hmgb1ΔLysM) HMGB1 的小鼠，我们探索了 HMGB1 在结肠炎和结肠炎相关结直肠癌不同发病机制中的功能。结果 HMGB1 在人类炎症性肠病和胃肠道癌症中过度表达，并且 HMGB1 蛋白定位于人类和啮齿动物的结肠炎和结直肠癌标本中的肠细胞和基质细胞中。如前所述，肠上皮细胞 HMGB1 缺乏会加重化学引起的严重肠道损伤，但不会加重小鼠柠檬酸杆菌或 T 细胞转移性结肠炎。 HMGB1 缺陷的肠上皮细胞和类器官在体外不会表现出异常的凋亡或自噬活性、改变的增殖或迁移能力、异常的肠道通透性或异常的 DSS 诱导的类器官炎症。相反，我们在结肠炎早期观察到 Hmgb1ΔIEC 中肠上皮和浸润骨髓细胞的体内重编程发生改变，表明 HMGB1 介导的旁分泌损伤信号传导。在 Apc+/min 模型中，Hmgb1ΔIEC 比野生型具有更高的 CRC 负担，而 Hmgb1ΔLysM 中的炎症性 CRC 减弱。 Hmgb1ΔIEC 和 Hmgb1ΔLysM 癌症的细胞和分子表型表明，免疫信号传导和细胞外基质重塑通过 HMGB1 进行环境依赖性转录调节。结论 肠上皮细胞和骨髓细胞通过 HMGB1 环境依赖性地调节宿主对严重结肠炎和适应不良肠道伤口愈合的反应。