Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4

TLDR

In celiac disease, ingestion of wheat, barley, or rye triggers small intestinal inflammation, with gluten provoking a Th1‑mediated adaptive response in HLA‑DQ2/8 carriers, while the role of innate immunity remains poorly understood. The study aims to identify the wheat α‑amylase/trypsin inhibitors CM3 and 0.19 as potent activators of innate immunity in monocytes, macrophages, and dendritic cells. ATIs activate the TLR4‑MD2‑CD14 complex, up‑regulating maturation markers and inducing proinflammatory cytokine release in cells from celiac and nonceliac patients and in celiac biopsies. Mice lacking TLR4 or its signaling are protected from intestinal and systemic responses to oral ATIs, establishing cereal ATIs as novel contributors to celiac disease that may also drive inflammation in other intestinal and nonintestinal disorders.

Abstract

Ingestion of wheat, barley, or rye triggers small intestinal inflammation in patients with celiac disease. Specifically, the storage proteins of these cereals (gluten) elicit an adaptive Th1-mediated immune response in individuals carrying HLA-DQ2 or HLA-DQ8 as major genetic predisposition. This well-defined role of adaptive immunity contrasts with an ill-defined component of innate immunity in celiac disease. We identify the α-amylase/trypsin inhibitors (ATIs) CM3 and 0.19, pest resistance molecules in wheat, as strong activators of innate immune responses in monocytes, macrophages, and dendritic cells. ATIs engage the TLR4-MD2-CD14 complex and lead to up-regulation of maturation markers and elicit release of proinflammatory cytokines in cells from celiac and nonceliac patients and in celiac patients' biopsies. Mice deficient in TLR4 or TLR4 signaling are protected from intestinal and systemic immune responses upon oral challenge with ATIs. These findings define cereal ATIs as novel contributors to celiac disease. Moreover, ATIs may fuel inflammation and immune reactions in other intestinal and nonintestinal immune disorders.