Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada.
Children Research Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, Manitoba, Canada.
Br J Pharmacol. 2019 May;176(9):1235-1250. doi: 10.1111/bph.14614. Epub 2019 Apr 1.
An alteration in the communication between the innate and adaptive immune cells is a hallmark of ulcerative colitis (UC). Semaphorin-3E (SEMA3E), a secreted guidance protein, regulates various immune responses.
We investigated the expression of SEMA3E in colonic biopsies of active UC patients and its mechanisms in Sema3e mice using an experimental model of UC.
SEMA3E level was decreased in active UC patients and negatively correlated with pro-inflammatory mediators. Colonic expression of SEMA3E was reduced in colitic Sema3e mice, and recombinant (rec-) Plexin-D1 treatment exacerbated disease severity. In vivo rec-SEMA3E treatment restored SEMA3E level in colitic Sema3e mice. In Sema3e mice, disease severity was increased, and rec-SEMA3E ameliorated these effects. Lack of Sema3e increased the expression of CD11c and CD86 markers. Colitic Sema3e splenocytes and splenic CD11c cells produced more IL-12/23 and IFN-γ compared to Sema3e , and rec-SEMA3E reduced their release as much as NF-κB inhibitors, whereas an NF-κB activator increased their production and attenuated the effect of rec-SEMA3E. Colitic Sema3e splenic CD11c /CD4 CD25 T-cell co-cultures produced higher concentrations of IFN-γ and IL-17 when compared to colitic Sema3e splenic cell co-cultures, and rec-SEMA3E decreased these effects. In vitro, anti-IL-12p19 and -12p35 antibodies and rec-IL-12 and -23 treatment confirmed the crosstalk between CD11c and CD4 CD25 T-cells.
SEMA3E is reduced in colitis and modulates colonic inflammation by regulating the interaction between CD11c and CD4 CD25 T-cells via an NF-κB-dependent mechanism. Thus, SEMA3E could be a potential therapeutic target for UC patients.
固有免疫细胞和适应性免疫细胞之间通讯的改变是溃疡性结肠炎（UC）的一个标志。信号素 3E（SEMA3E）是一种分泌的导向蛋白，调节各种免疫反应。
我们使用 UC 实验模型研究了活动期 UC 患者结肠活检中 SEMA3E 的表达及其在 Sema3e 小鼠中的机制。
SEMA3E 水平在活动期 UC 患者中降低，并与促炎介质呈负相关。在 colitic Sema3e 小鼠中，SEMA3E 的结肠表达减少，而重组（rec-）Plexin-D1 治疗则加重了疾病严重程度。体内 rec-SEMA3E 治疗可恢复 colitic Sema3e 小鼠中的 SEMA3E 水平。在 Sema3e 小鼠中，疾病严重程度增加，rec-SEMA3E 可改善这些作用。缺乏 Sema3e 会增加 CD11c 和 CD86 标志物的表达。与 Sema3e 相比，colitic Sema3e 脾细胞和脾 CD11c 细胞产生更多的 IL-12/23 和 IFN-γ，rec-SEMA3E 降低其释放量与 NF-κB 抑制剂一样多，而 NF-κB 激活剂则增加其产生并减弱 rec-SEMA3E 的作用。与 colitic Sema3e 脾细胞共培养相比，colitic Sema3e 脾 CD11c / CD4 CD25 T 细胞共培养产生更高浓度的 IFN-γ和 IL-17，rec-SEMA3E 降低了这些作用。体外，抗 IL-12p19 和 -12p35 抗体和 rec-IL-12 和 -23 治疗证实了 CD11c 和 CD4 CD25 T 细胞之间的串扰。
SEMA3E 在结肠炎中减少，并通过 NF-κB 依赖性机制调节 CD11c 和 CD4 CD25 T 细胞之间的相互作用来调节结肠炎症。因此，SEMA3E 可能是 UC 患者的潜在治疗靶点。
