Control of Intestinal Type 3 Immunity by the Unfolded Protein Response Sensor Inositol-Requiring Enzyme 1α in...

The unfolded protein response is an essential cellular program maintaining intestinal homeostasis by acting on several cell types. However, whether the unfolded protein response sensor inositol-requiring enzyme 1α acts on dendritic cells and other antigen-presenting cells for shaping intestinal immunity remains poorly defined.

Here, we dissect the role of the endoribonuclease domain of the unfolded protein response sensor inositol-requiring enzyme 1α in intestinal CD11c⁺ antigen-presenting cells, using inositol-requiring enzyme 1α endoribonuclease reporter mice and conditional loss-of-function models for inositol-requiring enzyme 1α and its downstream transcription factor, the X-box binding protein 1 spliced.

We identify robust inositol-requiring enzyme 1α endoribonuclease activity in intestinal conventional dendritic cell subsets, dendritic cells associated with crypto patches and isolated lymphoid follicles, and macrophages, independently of microbial signals. Targeted ablation of inositol-requiring enzyme 1α endoribonuclease in the intestinal CD11c⁺ compartment provoked spontaneous features of type 3 immunity in the small intestine, characterized by increased antimicrobial peptides and neutrophil recruitment, as well as elevated production of interleukin17 and interleukin 22 by T helper 17 cells and group 3 innate lymphoid cells. This dysregulated activation required inositol-requiring enzyme 1α endoribonuclease but occurred independently of X-box binding protein 1 spliced, implicating regulated inositol-requiring enzyme 1α-dependent decay rather than canonical X-box binding protein 1 spliced signaling. Mechanistically, distinct inositol-requiring enzyme 1α endoribonuclease-deficient intestinal antigen-presenting cell subtypes such as conventional dendritic cells exhibited increased Il6, Il1b, and Ccl22 transcript levels, whereas conventional dendritic cells and dendritic cells associated with crypto patches and isolated lymphoid follicles showed marked reductions in interleukin22BP expression, a profile known to increase interleukin22 bioavailability and enhance T helper 17 cell-group 3 innate lymphoid cell responses.

Collectively, our findings uncover inositol-requiring enzyme 1α endoribonuclease in intestinal CD11c⁺ antigen-presenting cell subtypes as a critical checkpoint restraining type 3 immunity and maintaining intestinal immunity in steady state, highlighting its potential as therapeutic target for intestinal inflammation.