PDF(Pubmed)
Abstract：
Group 3 innate lymphoid cells (ILC3s) play key roles in intestinal inflammation. Olfactomedin 4 (OLFM4) is highly expressed in the colon and has a potential role in dextran sodium sulfate-induced colitis. However, the detailed mechanisms underlying the effects of OLFM4 on ILC3-mediated colitis remain unclear. In this study, we identify OLFM4 as a positive regulator of IL-22+ILC3. OLFM4 expression in colonic ILC3s increases substantially during intestinal inflammation in humans and mice. Compared to littermate controls, OLFM4-deficient (OLFM4-/-) mice are more susceptible to bacterial infection and display greater resistance to anti-CD40 induced innate colitis, together with impaired IL-22 production by ILC3, and ILC3s from OLFM4-/-mice are defective in pathogen resistance. Besides, mice with OLFM4 deficiency in the RORγt compartment exhibit the same trend as in OLFM4-/-mice, including colonic inflammation and IL-22 production. Mechanistically, the decrease in IL-22+ILC3 caused by OLFM4 deficiency involves the apoptosis signal-regulating kinase 1 (ASK1)- p38 MAPK signaling-dependent downregulation of RAR-related orphan receptor gamma (RORγt) protein. The OLFM4-metadherin (MTDH) complex upregulates p38/RORγt signaling, which is necessary for IL-22+ILC3 activation. The findings indicate that OLFM4 is a novel regulator of IL-22+ILC3 and essential for modulating intestinal inflammation and tissue homeostasis.
摘要：
第3组先天淋巴样细胞(ILC3s)在肠道炎症中起关键作用。Olfactomedin4（OLFM4）在结肠中高表达，在葡聚糖硫酸钠诱导的结肠炎中具有潜在作用。然而,OLFM4对ILC3介导的结肠炎影响的详细机制尚不清楚.在这项研究中,我们确定OLFM4是IL-22+ILC3的正调节因子。在人和小鼠的肠道炎症期间,结肠ILC3s中的OLFM4表达显著增加。与同窝对照相比，OLFM4缺陷（OLFM4-/-）小鼠更容易受到细菌感染，并显示出抗CD40诱导的先天性结肠炎更大的抵抗力，连同ILC3的IL-22产生受损，OLFM4-/-小鼠的ILC3在病原体抗性方面存在缺陷。此外,RORγt区室中OLFM4缺乏的小鼠表现出与OLFM4-/-小鼠相同的趋势，包括结肠炎症和IL-22的产生。机械上,由OLFM4缺乏引起的IL-22ILC3的减少涉及RAR相关孤儿受体γ（RORγt）蛋白的凋亡信号调节激酶1（ASK1）-p38MAPK信号传导依赖性下调。OLFM4-metadherin(MTDH)复合物上调p38/RORγt信号,这是IL-22+ILC3激活所必需的。研究结果表明，OLFM4是IL-22ILC3的新型调节剂，对于调节肠道炎症和组织稳态至关重要。
