Monzani Romina, Gagliardi Mara, Saverio Valentina, Clemente Nausicaa, Monzani Alice, Rabbone Ivana, Nigrelli Francesca, Pellizzaro Samuele, Ferrario Emanuele, Saettone Silvia, Pagano Nico, De Leo Luigina, Lim Dmitry, Sblattero Daniele, Corazzari Marco
Department of Health Sciences, School of Medicine, Center for Translational Research on Autoimmune and Allergic Disease (CAAD), University of Piemonte Orientale, Novara, Italy.
Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Piemonte Orientale, Novara, Italy.
Biol Direct. 2025 Mar 31;20(1):39. doi: 10.1186/s13062-025-00633-y.
Coeliac disease is an autoimmune disease that is primarily associated with chronic inflammation of the gut, but can also affect organs outside the gut, from the liver to the skin and CNS. The disease is triggered in predisposed individuals by a peptide mixture (PT) derived from the digestion of gliadin, a component of wheat, which is ingested with food. Although the induction of endoplasmic reticulum stress in intestinal epithelial cells (IECs) upon exposure to PT is known, the underlying molecular mechanisms remain unclear. Identifying the key players in this signaling pathway could therefore help to develop a new effective therapeutic strategy for the treatment of CD patients.
Two CD models were used to identify the molecular mechanism linking extracellular PT and endoplasmic reticulum (ER) stress in the IECs of predisposed individuals exposed to gliadin. These models were an in vitro model based on CaCo-2 cells and an ex vivo model based on our previously described gut ex vivo system (GEVS), both exposed to PT.
Our results clearly show that the interaction of gliadin peptides with the transmembrane CXCR3 receptor on IECs leads to a rapid induction of PLC activity that generates IP3 molecules. This second messenger binds to the IP3R located in ER membranes, resulting in calcium efflux from the organelle.
The PT-dependent ER stress observed in the IECs of CD patients results from the excessive release of calcium from the ER. Importantly, inhibition of this signaling pathway abrogates ER stress, which in turn attenuates downstream signs of CD, such as TG2 expression and gut permeability dysregulation, as well as inhibits inflammation.
乳糜泻是一种自身免疫性疾病，主要与肠道慢性炎症相关，但也可影响从肝脏到皮肤和中枢神经系统等肠道外器官。该病由摄入食物中含有的小麦成分麦醇溶蛋白消化产生的肽混合物（PT）在易感个体中引发。虽然已知暴露于PT后肠道上皮细胞（IECs）会诱导内质网应激，但其潜在分子机制仍不清楚。因此，确定该信号通路中的关键因子有助于开发一种治疗乳糜泻患者的新的有效治疗策略。
使用两种乳糜泻模型来确定在暴露于麦醇溶蛋白的易感个体的IECs中，连接细胞外PT与内质网（ER）应激的分子机制。这些模型一种是基于CaCo-2细胞的体外模型，另一种是基于我们先前描述的肠道离体系统（GEVS）的离体模型，二者均暴露于PT。
我们的结果清楚地表明，麦醇溶蛋白肽与IECs上的跨膜CXCR3受体相互作用导致PLC活性迅速诱导，产生IP3分子。这种第二信使与位于内质网膜上的IP3R结合，导致细胞器内的钙外流。
在乳糜泻患者的IECs中观察到的PT依赖性内质网应激是由内质网中钙的过度释放引起的。重要的是，抑制该信号通路可消除内质网应激，进而减轻乳糜泻的下游体征，如TG2表达和肠道通透性失调，以及抑制炎症。
