Uncovering the role of TREM-1 in celiac disease: in silico insights into the recognition of gluten-derived peptides and inflammatory mechanisms

Abstract

Background: Celiac disease (CD) is a chronic enteropathy characterized by a permanent intolerance to gluten. While CD has been associated with heightened T cell responses and the involvement of distinct innate immunity components, the role of the triggering receptor expressed on myeloid cells (TREM) family in this disease remains unclear. Thus, as TREM-1 has already been implicated in other inflammatory bowel diseases, and given its role in the amplification of inflammation, we hypothesized that it might play a role in the pathophysiology of CD. Methods and results: the STRING tool was used to predict protein-protein interaction networks between TREM-1 and CD signaling pathways. Then, molecular docking and molecular dynamics simulations were conducted to explore potential interactions between TREM-1 and different peptides derived from alpha-gliadin (25-mer, 33- mer and p31-43). Finally, we used transcriptomic data, available from public repositories, to assess TREM1 gene expression, and genes involved in its signaling pathway, in CD patients. Our results found an association between TREM-1 and CD markers, with STRING analysis, and the in silico simulations suggesting that the receptor might recognize the alpha-gliadin peptides, with the TREM-1/p31-43 interaction as the most likely interaction to occur biologically. Furthermore, TREM1 and its signaling pathway were increased in patients with active CD, while in those in clinical remission, the expression levels were similar to healthy controls. Conclusions: collectively, our findings suggest that TREM-1 might recognize alpha-gliadin derived peptides, and TREM-1’s activation may contribute to the intestinal inflammation observed in CD.