IEC-intrinsic IL-1R signaling holds dual roles in regulating intestinal homeostasis and inflammation

Intestinal epithelial cells (IECs) constitute a critical first line of defense against microbes. While IECs are known to respond to various microbial signals, the precise upstream cues regulating diverse IEC responses are not clear. Here, we discover a dual role for IEC-intrinsic interleukin-1 receptor (IL-1R) signaling in regulating intestinal homeostasis and inflammation. Absence of IL-1R in epithelial cells abrogates a homeostatic antimicrobial program including production of antimicrobial peptides (AMPs). Mice deficient for IEC-intrinsic IL-1R are unable to clear Citrobacter rodentium (C. rodentium) but are protected from DSS-induced colitis. Mechanistically, IL-1R signaling enhances IL-22R-induced signal transducer and activator of transcription 3 (STAT3) phosphorylation in IECs leading to elevated production of AMPs. IL-1R signaling in IECs also directly induces expression of chemokines as well as genes involved in the production of reactive oxygen species. Our findings establish a protective role for IEC-intrinsic IL-1R signaling in combating infections but a detrimental role during colitis induced by epithelial damage. This study characterizes the dual role of IL-1R signaling in IECs during C. rodentium infection and DSS-induced colitis. IEC-intrinsic IL-1R signaling enhances IL-22-induced AMPs for protection but contributes to damage-induced inflammation through induction of chemokines and ROS genes.

Automated summary

Intestinal epithelial cells (IECs) are critical in defending against microbes, with interleukin-1 receptor (IL-1R) signaling playing a dual role in regulating intestinal homeostasis and inflammation. IL-1R enhances IL-22-induced antimicrobial peptides (AMPs) production in IECs, providing protection against infections. However, IL-1R signaling in IECs also induces chemokines and reactive oxygen species genes, contributing to inflammation during colitis induced by epithelial damage.