# Neutrophil Interactions with Intestinal Epithelial Cells

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $508,401

## Abstract

Abstract
A major component of many inflammatory diseases of mucosal surfaces, particularly in the intestine, is
migration of large numbers of neutrophils (PMN) across the epithelium and accumulation within a
lumen. In such conditions, disease symptoms are complex but directly related to leukocyte effects on
the epithelial barrier and epithelial cell function. While much has been learned about mechanisms of
leukocyte emigration from the circulation, much less is known about the receptors that regulate
leukocyte interactions with the intestinal epithelium. In our studies, we have shown that a sequential
series of adhesive steps are necessary for PMN to traverse the epithelium in a polarized manner that
begins with interactions with the basolateral membrane and ends at the level of the apical or luminal
membrane. However, many of the details of the transepithelial migration cascade and functional
consequences of such remain poorly understood despite the clear link to many inflammatory diseases.
This proposal will focus on functional consequences of PMN interactions with specific receptors at the
level of the tight junction and apical/luminal epithelial membrane. We will extend recently obtained
evidence linking binding interactions between PMN expressed JAM like protein (JAML) and the tight
junction associated coxsackie and adenovirus receptor (CAR) with pro-inflammatory effects on
epithelial homeostasis. Our studies also suggest that expression of the prototypic JAM protein family
member termed JAM-A on leukocytes and epithelial cells is important in preventing pathologic
inflammation in the intestine, however the relative contributions of epithelial and leukocyte expressed
JAM-A to regulating intestinal mucosal homeostasis are not defined. Mechanisms and relative
contributions of JAM-A in leukocytes and epithelial cells to development of experimental colitis will be
explored. We have also determined that at late stages of the PMN transepithelial migration response
there are binding interactions between PMN and the apical epithelial membrane mediated by specific
glycan epitopes displayed on the transmembrane protein CD44v6. Such binding interactions result in
epithelial functional responses that positively regulate epithelial barrier function. Details of the
mechanisms behind such PMN interactions with epithelial cells are lacking despite the potential
importance of resultant epithelial signaling responses in promoting mucosal health and healing.
Experiments in this proposal will provide insights into these important issues as well as new ideas for
the development of agents that might be used as anti-inflammatories in a tissue targeted manner as
well as for enhanced mucosal wound healing.

## Key facts

- **NIH application ID:** 9964772
- **Project number:** 5R01DK072564-25
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** CHARLES A PARKOS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $508,401
- **Award type:** 5
- **Project period:** 1995-04-05 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9964772

## Citation

> US National Institutes of Health, RePORTER application 9964772, Neutrophil Interactions with Intestinal Epithelial Cells (5R01DK072564-25). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9964772. Licensed CC0.

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