# Paneth cell-specific IL-22Ra1 signaling in mucosal host defense

> **NIH NIH R21** · STATE UNIVERSITY NEW YORK STONY BROOK · 2020 · $196,076

## Abstract

Interleukin (IL)-22, which is derived from innate lymphoid cells (ILC)-3 and Th17 cells, plays an important role in
intestinal host defense since mice deficient in IL-22 or its receptor, IL-22Ra1, are highly susceptible to multiple
models of intestinal inflammation. In the past 10 years substantial progress has been made in our understanding
of the IL-22-mediated mucosal host defense responses in the intestine; however, serious gaps in our knowledge
remain. The pleiotropic effects of IL-22, coupled with the diverse array of intestinal cell types that express IL-
22Ra1, limit our ability to target this pathway therapeutically. It remains unclear how IL-22 interacts with
functionally distinct epithelial cell lineages (absorptive or secretory) and intestinal stem cells (ISCs). The goal of
this proposal is to understand whether IL-22Ra1 signaling in Paneth and/or intestinal stem cell (ISCs) regulates
IL-22-mediated protection. We will assess the mechanistic nature of that protection on distinct epithelial
compartments using cell-specific knockout mice and recombinant IL-22.Fc protein approaches. Towards this
end, we generated 1) entire gut epithelium, 2) Lgr5+ ISCs, and 3) Paneth cell-specific conditional IL-22Ra1
knockout mice. We have accumulated critical data that lack of intestinal IL-22Ra1 signaling leads to a defect in
Paneth cell-specific functions as well as enhanced susceptibility to Salmonella Typhimurium. Thus, based on
the strength of our preliminary results, we hypothesize that IL-22Ra1 signaling in Paneth cells modulates
intestinal host defense by regulating post-translational modifications of a-defensins and maintaining ISCs niche.
In specific Aim 1, we will determine whether IL-22Ra1 signaling in Paneth cells regulates post-translational
modification of a-defensins and maintains ISCs niche. In Aim 2, we will investigate whether Paneth, ISCs and/or
absorptive enterocytes-specific role of IL-22Ra1 signaling is required to control S. Typhimurium-induced
inflammation. These studies will provide critical new mechanistic information about specific cellular niches of IL-
22Ra1-signaling in the gut and their involvement in disease development, maintenance and therapeutic
outcomes.

## Key facts

- **NIH application ID:** 9877121
- **Project number:** 1R21AI149257-01
- **Recipient organization:** STATE UNIVERSITY NEW YORK STONY BROOK
- **Principal Investigator:** Pawan Kumar
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $196,076
- **Award type:** 1
- **Project period:** 2020-02-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9877121

## Citation

> US National Institutes of Health, RePORTER application 9877121, Paneth cell-specific IL-22Ra1 signaling in mucosal host defense (1R21AI149257-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9877121. Licensed CC0.

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