# Neuroendocrine regulation of intestinal epithelial immunity in C. elegans

> **NIH NIH R21** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2022 · $209,375

## Abstract

PROJECT SUMMARY
The human intestine is densely innervated, and it is becoming increasingly clear that the enteric nervous
system plays a key role in maintaining immune homeostasis. However, disentangling the contribution of
individual sensory neurons in the regulation of intestinal inflammation has been challenging, owing to the
marked complexity of both neural-immune interactions and the microbial communities in the intestine. We
made a surprising discovery that olfactory receptor development is linked to innate immune regulation in the
intestine. From a forward genetic screen for regulators of host immune defenses in the nematode C. elegans,
we found that loss-of-function mutations in the olfactory neuron gene olrn-1 caused aberrant immune
hyperactivation in the intestinal epithelium. During nematode development, olrn-1 is required to program the
expression of neuronal receptors in one particular type of sensory neuron, the amphid wing C (AWC) neurons,
which allows odor discrimination and chemotaxis. During nematode development, low activity of OLRN-1
induces p38 signaling within AWC neurons themselves to promote olfactory receptor expression. We
demonstrated that low OLRN-1 activity also de-represses the p38 PMK-1 innate immune pathway in the
intestine to promote immune effector transcription, increased clearance of an intestinal pathogen, and
resistance to bacterial infection. However, unchecked immune activation in olrn-1 mutants is toxic to nematode
development, a physiological process that our laboratory, and others, have previously shown is particularly
vulnerable to perturbations in intestinal immune homeostasis. These data suggest that OLRN-1-expressing
sensory neurons in C. elegans optimize the degree of p38 PMK-1 immune activation, which is essential both to
handle challenges from bacterial pathogens and to prevent the deleterious consequences of unchecked
immune activation. However, it is not known how OLRN-1 in AWC sensory neurons communicates with the
p38 PMK-1 pathway in the intestine to promote immune homeostasis.
 The central hypothesis of this proposal is that AWC olfactory neurons promote immune homeostasis
through the neuroendocrine-mediated suppression of the intestinal p38 PMK-1 innate immune pathway. In
support of our central hypothesis, the forward genetic screen for novel immune regulators, which uncovered
olrn-1 mutants, also identified a loss-of-function mutant allele in an intestinal neuropeptide G protein-coupled
receptor. We propose that this receptor and a cognate neuropeptide hormone act downstream of AWC sensory
neurons to regulate anti-pathogen responses in C. elegans. These studies will characterize the genetic
mechanisms that link sensory neuron activity to the regulation of immunity in the intestinal epithelium. We
expect that these insights will reveal ancestral strategies of healthy immune control and provide fundamental
insights into intestinal immune homeostasis that may be directly applicable to mammalia...

## Key facts

- **NIH application ID:** 10412133
- **Project number:** 5R21AI163430-02
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Read Pukkila-Worley
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $209,375
- **Award type:** 5
- **Project period:** 2021-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10412133

## Citation

> US National Institutes of Health, RePORTER application 10412133, Neuroendocrine regulation of intestinal epithelial immunity in C. elegans (5R21AI163430-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10412133. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*