IL-33/regulatory T cell axis triggers the development of a tumor-promoting immune environment in chronic inflammation
IL-33/regulatory T cell axis triggers the development of a tumor-promoting immune environment in chronic inflammation
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DOI：
10.1073/pnas.1815016116
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发表时间：
2019-02-12
影响因子：
11.1
通讯作者：
Demehri, Shadmehr
中科院分区：
文献类型：
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作者：
Ameri, Amir H.;Tuchayi, Sara Moradi;Demehri, Shadmehr
慢性炎症的促癌潜力是公认的；然而，这种免疫环境发展的潜在机制尚不清楚。研究从急性的、肿瘤抑制的到慢性的、促进肿瘤的过敏性接触性皮炎(ACD)的转变，揭示了促进肿瘤的慢性炎症是如何发展的。在急性ACD向慢性ACD转变之前，表皮来源的IL-33上调及其诱导的调节性T细胞(Treg)在皮肤中积聚，并触发了慢性ACD促肿瘤免疫环境。与野生型对照相比，IL-33缺失的小鼠可预防慢性急性皮肤病及其皮肤癌后遗症(P=0.0002)。IL-33‘S对Treg的直接信号是皮肤促癌免疫环境的形成所必需的。在结肠炎模型中，IL-33-Treg信号对于慢性结肠炎及其相关的结直肠癌的发展也是必需的(P<；0.0001)。在有癌症倾向的慢性炎症性疾病的患者中，IL-33和Tregs的显著增加标志着病变周围的皮肤和结肠。我们的发现阐明了IL-33/Treg轴在慢性炎症性疾病中创建促进肿瘤的免疫环境中的作用，并为高危患者的癌症预防和治疗提供了治疗靶点。
Chronic inflammation's tumor-promoting potential is well-recognized; however, the mechanism underlying the development of this immune environment is unknown. Studying the transition from acute, tumor-suppressive to chronic, tumor-promoting allergic contact dermatitis (ACD) revealed how tumor-promoting chronic inflammation develops. Epidermis-derived interleukin (IL)-33 up-regulation and its induction of regulatory T cell (Treg) accumulation in the skin preceded the transition from acute to chronic ACD and triggered the tumor-promoting immune environment in chronic ACD. Mice lacking IL-33 were protected from chronic ACD and its skin cancer sequela compared with wild-type controls (P = 0.0002). IL-33's direct signaling onto Tregs was required for the development of the tumor-promoting immune environment in the skin. IL-33-Treg signaling was also required for chronic colitis and its associated colorectal cancer development in a colitis model (P < 0.0001). Significantly increased IL-33 and Tregs marked the perilesional skin and colon in patients with cancer-prone chronic inflammatory diseases. Our findings elucidate the role of the IL-33/Treg axis in creating a tumor-promoting immune environment in chronic inflammatory diseases and suggest therapeutic targets for cancer prevention and treatment in high-risk patients.