Innate recognition of the microbiota by Toll-like Receptor-1 promotes epithelial homeostasis and prevents chronic inflammation

• Published in: The Journal of immunology (1950) 2018-05, Vol.201 (1), p.230-242
• Main Authors: Kamdar, Karishma, Johnson, Andrew M. F., Chac, Denise, Myers, Kalisa, Kulur, Vrishika, Truevillian, Kyle, DePaolo, R. William
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1701216

There is crosstalk between the intestinal epithelium and the microbiota that functions to maintain a tightly regulated microenvironment and prevent chronic inflammation. This communication is partly mediated through the recognition of bacterial proteins by host encoded innate receptors, such as Toll-like Receptors. However, studies examining the role of Toll-like Receptor signaling on colonic homeostasis have given variable and conflicting results. Despite its critical role in mediating immunity during enteric infection of the small intestine, TLR1-mediated recognition of microbiota-derived ligands and their influence on colonic homeostasis has not been well studied. Here, we demonstrate that defective TLR1 recognition of the microbiome by epithelial cells results in disruption of crypt homeostasis specifically within the secretory cell compartment, including a defect in the mucus layer, ectopic Paneth cells in the colon and an increase in the number of rapidly dividing cells at the base of the crypt. As a consequence of the perturbed epithelial barrier, we found an increase in mucosal-associated and translocated commensal bacteria and chronic low-grade inflammation characterized by an increase in lineage-negative, Sca1 + Thy1 hi innate lymphoid-like cells that exacerbate inflammation and worsen outcomes in a model of colonic injury and repair. Our findings demonstrate that sensing of the microbiota by Toll-like Receptor-1 may provide key signals that regulate the colonic epithelium thereby limiting inflammation through the prevention of bacterial attachment to the mucosa and exposure to the underlying immune system.