Abstract
Abstract Inflammatory bowel disease, while multifactorial, is largely characterized by an exacerbated intestinal immune activation. However, the critical mechanisms regulating immune activation remain to be fully defined. We have previously reported that a member of the TNF superfamily, TNFSF14/LIGHT, is required for prevention of severe disease in a mouse model of dextran sodium sulfate (DSS) induced colitis. Additionally, antibody-mediated blocking of lymphotoxin beta receptor (LTβR), which recognizes LIGHT, also led to exacerbated colitis pathogenesis. Thus, we aimed to determine the cell type(s) and mechanism critical to LTβR mediated exacerbation of DSS driven colitis. Employing the use of LTβRflox/flox mice and appropriate Cre strains, we were able to evaluate the role of LTβR signaling during DSS-induced colitis in a variety of immune and intestinal cell types. For all experiments, body weight, colon length and intestinal histopathology were assessed. These studies revealed that neutrophils were the critical LTβR expressing cell type and that specific deletion of neutrophil LTβR expression, via MRP8 Cre, resulted in exacerbated DSS-induced colitis similar to that in LIGHT−/− mice. RNASeq analysis of neutrophils revealed alterations in cellular metabolism and mitochondrial function, further confirmed through ex vivo analysis of LTβR deficient neutrophils, which had increased mitochondria. In sum, our results demonstrate that neutrophil LTβR activation, likely through LIGHT signaling, plays a critical role in the immune activation associated with DSS-induced colitis.
Published Version
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call