TLR9 is important for protection against intestinal damage and for intestinal repair

Abstract

Toll-like receptors (TLRs) are innate receptors critical for host defense, and play a role in normal biological processes. For example, host DNA, a TLR9 ligand, stimulates epithelial repair following skin wounding. TLR signaling also plays a crucial role in regulating intestinal homeostasis. We therefore asked whether TLR9 is important for intestinal wound repair using a dextran sulfate sodium (DSS)-induced intestinal damage and repair model. We showed that TLR9-deficient mice are more susceptible to DSS, and exhibited delayed wound repair at both the clinical and histologic levels. TLR9-deficient mice showed reduced gene expression of hairy enhancer of split 1, an intestinal progenitor cell differentiation factor, and vascular endothelial growth factor, a growth factor important for epithelial cell restitution. Therefore, we conclude that TLR stimulation may play a normal role in regulating intestinal homeostasis and could potentially be a novel therapeutic target to enhance intestinal wound repair in inflammatory bowel diseases.

Fasting-Mimicking Diet Modulates Microbiota and Promotes Intestinal Regeneration to Reduce Inflammatory Bowel Disease Pathology

“…A reduction in colon length is a marker of intestinal damage after DSS treatment and a phenotypic feature used to assess IBD severity (Rose et al, 2012). After 4 DSS cycles, colon length was shortened to an average of 6.5 cm from an average of 7.6 cm in the Naive group (p < 0.01) (Figures 1G and 1H).…”

A whole-blood RNA transcript-based gene signature is associated with the development of CTLA-4 blockade-related diarrhea in patients with advanced melanoma treated with the checkpoint inhibitor tremelimumab

“…Despite this gene signature being predictive for diarrhea, three of the enhancer variable genes appear to either directly or indirectly have a protective effect against diarrhea in other settings. TLR9 protects against intestinal epithelium damage and thus preventing some forms of diarrhea [ 26 ]. Loss of IL-18 bp expression is associated with severe colitis and loss of mature goblet cells in mice [ 27 ].…”

Dextran Sulfate Sodium (DSS)‐Induced Colitis in Mice

“…In addition, these TLR ligands did not protect against DSS-induced colitis in mice deficient in respective TLRs (Rakoff-Nahoum et al, 2004). Similarly, systemic administration of Poly (I:C), flagellin, CpG DNA, and muramyl dipeptide, respectively recognized by TLRs 3, 5 and 9 and NOD2, provide significant protection against DSS-induced colitis (Rose et al, 2012; Vijay-Kumar et al, 2008; Vijay-Kumar et al, 2007; Watanabe et al, 2008). Further, the development of severe DSS-induced colitis is exacerbated in MyD88 deficient mice lacking all TLR signaling (with the exception of TLR3), including that required for production of the inflammasome cytokines IL-1β and IL-18 (Rakoff-Nahoum et al, 2004).…”