JAK/STAT信号通路在肠黏膜再生及调节辅助性T细胞应答中的研究进展

Research Progress of JAK/STAT Signal Pathway Regulating Intestinal Mucosal Regeneration and Helper T Cell Response

肠道是机体内外环境的交汇点,易遭受各种有毒有害物质的刺激,导致上皮结构受损、功能紊乱和微生态失调,进而造成畜禽生长性能下降,经济效益降低。位于隐窝基底部的肠道干细胞(intestinal stem cell,ISCs)驱动的肠上皮细胞更新是维持上皮结构的动力所在,也是肠道损伤修复的必要途径。ISCs活性受微环境中各种分子信号的协同调控,而Janu激酶/信号转导与转录激活子(JAK/STAT)通路是多种细胞因子信号转导的共同途径。这些细胞因子可结合细胞膜上酪氨酸激酶相关受体,激活JAK,促进STAT磷酸化并入核,引起周期相关蛋白和抗凋亡蛋白等靶基因的转录,从而控制ISCs增殖、凋亡和分化命运,维持隐窝绒毛轴的有序结构。此外,ISCs周边的辅助型T细胞(Th细胞)通过分泌白细胞介素(interleukins,ILs)和干扰素(interferons,IFNs)与ISCs胞内的JAK/STAT信号通路串联,以实现肠细胞对损伤刺激做出快速应答,加速肠道干细胞分裂,促使肠上皮再生。作者重点阐述了JAK/STAT介导ISCs维持肠上皮结构与功能完整性以及Th细胞如何调节ISCs向功能细胞分化的作用机制,介绍了某些畜禽疾病发生时该信号通路的异常变化,并指出在下一步研究中可将肠道类器官等新兴研究模型纳入动物肠道发育和疾病诊断的研究和实践中。对JAK/STAT的精准调控,有望揭示隐窝-绒毛轴更新规律,为建立科学的营养调控技术方案、改善畜禽肠道及机体健康水平提供理论依据。

As the junction of the internal and external environment in the body,the intestine is susceptible to various toxic and harmful substances from outside,which leads to damage to the epithelial structure,function and microecosystem,and then reduces growth performance of animals and economic benefit.Intestinal stem cell(ISC)-driven intestinal cell renewal at the base of the crypt is the driving force for the epithelial structure and is necessary for the repair after intestinal injury.ISCs activity are synergistically regulated by various molecular signals in the ISCs microenvironment.And the Janu kinase/signal transducer and activator of transcription(JAK/STAT)pathway is a common pathway for multiple cytokine signals,which bind to tyrosine kinase-related receptors to activate JAK,and then phosphorylate STAT and trigger the transcription of target genes such as cycle-related and anti-apoptotic proteins to control ISCs proliferation,apoptosis,and differentiation fate and ultimately maintains the ordered structure of the crypt villi axis.In addition,helper T cells(Th cells)around the ISCs secrete interleukins(ILs)and interferons(IFNs)in crosstalk with the JAK/STAT signaling pathway in ISCs to achieve a rapid response of intestinal cells to injury stimuli,which accelerates ISCs division and promote intestinal epithelial regeneration.This review focused on the mechanisms of JAK/STAT-mediated ISCs in maintaining the structural and functional integrity of the intestinal epithelium and how Th cells regulate the differentiation of ISCs to functional cells.Meanwhile,the authors described abnormal changes in this signaling pathway during the occurrence of certain livestock and poultry diseases,and identify emerging research models such as intestinal organoids into the study and practice of animal intestinal development and disease diagnosis.The accurate control of JAK/STAT is expected to reveal the updating regularity of the crypt-villus axis and provide the theoretical basis for establishing the scientific nutritional technology scheme and improving intestinal health.