Instituto de Estudios Inmunológicos y Fisiopatológicos (CONICET), Universidad Nacional de La Plata, La Plata, Argentina.
Instituto de Fisicoquímica y Químicas Biológicas, Dr. Alejandro Paladini (CONICET), Universidad de Buenos Aires, Buenos Aires, Argentina.
Front Immunol. 2019 Jan 30;10:31. doi: 10.3389/fimmu.2019.00031. eCollection 2019.
Celiac disease (CD) is a chronic enteropathy elicited by a Th1 response to gluten peptides in the small intestine of genetically susceptible individuals. However, it remains unclear what drives the induction of inflammatory responses of this kind against harmless antigens in food. In a recent work, we have shown that the p31-43 peptide (p31-43) from α-gliadin can induce an innate immune response in the intestine and that this may initiate pathological adaptive immunity. The receptors and mechanisms responsible for the induction of innate immunity by p31-43 are unknown and here we present evidence that this may reflect conformational changes in the peptide that allow it to activate the NLRP3 inflammasome. Administration of p31-43, but not scrambled or inverted peptides, to normal mice induced enteropathy in the proximal small intestine, associated with increased production of type I interferon and mature IL-1β. P31-43 showed a sequence-specific spontaneous ability to form structured oligomers and aggregates and induced activation of the ASC speck complex. In parallel, the enteropathy induced by p31-43 did not occur in the absence of NLRP3 or caspase 1 and was inhibited by administration of the caspase 1 inhibitor Ac-YVAD-cmk. Collectively, these findings show that p31-43 gliadin has an intrinsic propensity to form oligomers which trigger the NLRP3 inflammasome and that this pathway is required for intestinal inflammation and pathology when p31-43 is administered orally to mice. This innate activation of the inflammasome may have important implications in the initial stages of CD pathogenesis.
乳糜泻（CD）是一种由遗传易感性个体小肠内麸质肽引发的 Th1 反应引起的慢性肠病。然而，目前尚不清楚是什么驱动了这种针对食物中无害抗原的炎症反应的诱导。在最近的一项工作中，我们已经表明，来自α-麦醇溶蛋白的 p31-43 肽（p31-43）可以在肠道中诱导先天免疫反应，并且这可能引发病理性适应性免疫。诱导 p31-43 先天免疫的受体和机制尚不清楚，在这里我们提出证据表明，这可能反映了肽的构象变化，使其能够激活 NLRP3 炎性体。向正常小鼠给予 p31-43 而不是乱序或倒置肽，可诱导近端小肠发生肠病，与 I 型干扰素和成熟的 IL-1β产量增加相关。p31-43 具有序列特异性的自发形成结构寡聚体和聚集体的能力 ，并诱导 ASC 斑点复合物的激活。平行地，p31-43 诱导的肠病在不存在 NLRP3 或半胱天冬酶 1 的情况下不会发生，并且可以通过给予半胱天冬酶 1 抑制剂 Ac-YVAD-cmk 来抑制。总的来说，这些发现表明，p31-43 麦醇溶蛋白具有形成寡聚体的固有倾向，这些寡聚体触发 NLRP3 炎性体，并且当 p31-43 被口服给予小鼠时，该途径是肠道炎症和病理学所必需的。这种炎性体的先天激活可能对 CD 发病机制的初始阶段具有重要意义。
