# Intestinal IL-17RA signaling and mucosal host defense

> **NIH NIH R01** · STATE UNIVERSITY NEW YORK STONY BROOK · 2020 · $412,984

## Abstract

Inflammatory bowel disease (IBD), which comprises Ulcerative Colitis (UC) and Crohn’s Disease (CD), is a
devastating disease that impacts millions of people in the United States. The underlying mechanisms leading
to IBD are poorly understood. Paneth cells and their antimicrobial products (a-defensins, lysozyme etc.) play a
critical role in small intestinal host defense and their dysregulation constitutes a pathogenic factor for CD. CD
patients have Paneth cell abnormalities, reduced expression of a-defensins and elevated levels of IL-17A in
the inflamed tissue. The IL-17A/IL-17F axis is a known driver of intestinal inflammatory and protective
responses in mouse models and human IBD, but little is known regarding the specific cellular niches of IL-
17A/F receptor signaling and the molecular mechanisms of IL-17A-mediated host defense in the intestines. We
were the first to show that the abrogation of intestinal IL-17A host defense responses leads to commensal
dysbiosis and dysregulated immune responses in the small intestine. Despite the myriad of gastrointestinal
tract responses to IL-17A stimulation, the literature has failed to elucidate whether the defense responses to
injury or infection are a result of direct stimulation to functionally distinct absorptive or secretory mature
epithelial cell types or if they are stem cell-derived consequences. Therefore, it is not known whether IL-17A
directly or indirectly modulates Paneth and other cell types effector function in the gut. We found that IL-17A/F
receptor (IL-17RA/IL-17RC) is expressed on functionally distinct absorptive cells (enterocytes), secretory cells
(Paneth), Lgr5+ intestinal stem cells (ISCs) and transit-amplifying (TA) progenitor cells of the intestine.
However, almost nothing is known regarding whether IL-17A directly or indirectly modulates Paneth cells, ISCs
and progenitor cells function. We now have compelling evidence suggesting that IL-17A directly regulates
unique and specific functions in Paneth cells, ISCs and ATOH1+ progenitor cells of intestine. ATOH1 is
required for lineage commitment of intestinal secretory cells, including Paneth cells. To investigate lineage-
specific function, we generated and validated entire gut epithelium (Villin-cre), Paneth cell (Defa6-cre) and
Atoh1-specific (Atoh1-cre) novel IL-17RA (Il17rafl/fl) conditional knockout mice. The proposed studies in Aim 1
will seek to understand the role of IL-17RA signaling in regulating ISC and Paneth cell function under
homeostatic conditions. In Aim 2, using multiple models of intestinal inflammation and our lineage-specific IL-
17RA conditional knockout mice, we will determine how IL-17A regulates unique and novel functions in specific
cell types in the small and large intestine, respectively. These studies will have a direct impact in IBD research
to understand the novel role of IL-17RA signaling major cell types of the small and large intestine. Completion
of these studies will provide a needed understandi...

## Key facts

- **NIH application ID:** 9963217
- **Project number:** 5R01DK121798-02
- **Recipient organization:** STATE UNIVERSITY NEW YORK STONY BROOK
- **Principal Investigator:** Pawan Kumar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $412,984
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9963217

## Citation

> US National Institutes of Health, RePORTER application 9963217, Intestinal IL-17RA signaling and mucosal host defense (5R01DK121798-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9963217. Licensed CC0.

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