Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Renal Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Cell Rep. 2019 Sep 24;28(13):3353-3366.e5. doi: 10.1016/j.celrep.2019.07.065.
Smad7, a negative regulator of TGF-β signaling, has been implicated in the pathogenesis and treatment of inflammatory bowel diseases (IBDs), including Crohn's disease (CD) and ulcerative colitis (UC). Here, we found that Smad7 mediates intestinal inflammation by limiting the PDL2/1-PD1 axis in dendritic cells (DCs) and CD4T cells. Smad7 deficiency in DCs promotes TGF-β responsiveness and the co-inhibitory molecules PDL2/1 on DCs, and it further imprints T cell-PD1 signaling to promote Treg differentiation. DC-specific Smad7 deletion mitigates DSS-induced colitis by inducing CD103PDL2/1DCs and Tregs. In addition, Smad7 deficiency in CD4T cells promotes PD1 and PD1-induced Tregs in vitro. The transfer of Smad7-deficient CD4T cells enhances Tregs in vivo and protects against T cell-mediated colitis. Furthermore, Smad7 antisense ameliorates DSS-induced UC, increasing TGF-β and PDL2/1-PD1 signaling. Enhancing PD1 signaling directly via Fc-fused PDL2/1 is also beneficial. Our results identify how Smad7 mediates intestinal inflammation and leverages these pathways therapeutically, providing additional strategies for IBD intervention.
Smad7 是 TGF-β信号的负调节剂，与炎症性肠病（IBD）的发病机制和治疗有关，包括克罗恩病（CD）和溃疡性结肠炎（UC）。在这里，我们发现 Smad7 通过限制树突状细胞（DC）和 CD4T 细胞中的 PDL2/1-PD1 轴来介导肠道炎症。DC 中 Smad7 的缺失促进了 TGF-β的反应性和 DC 上的共抑制分子 PDL2/1，进一步将 T 细胞-PD1 信号转导为促进 Treg 分化。DC 特异性 Smad7 缺失通过诱导 CD103PDL2/1DC 和 Treg 减轻 DSS 诱导的结肠炎。此外，CD4T 细胞中 Smad7 的缺失在体外促进 PD1 和 PD1 诱导的 Treg。Smad7 缺陷型 CD4T 细胞的转移增强了体内的 Treg，防止了 T 细胞介导的结肠炎。此外，Smad7 反义可改善 DSS 诱导的 UC，增加 TGF-β和 PDL2/1-PD1 信号。直接通过 Fc 融合的 PDL2/1 增强 PD1 信号也有益。我们的结果确定了 Smad7 如何介导肠道炎症，并利用这些途径进行治疗，为 IBD 的干预提供了额外的策略。
