# Control of Neutrophilic Inflammation in Intestinal Health and Disease

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2020 · $617,407

## Abstract

Summary:
The main objective of this proposal is to understand how neutrophils migrate across the intestinal
epithelia, toward the eventual goal of manipulating this process in pathologic conditions where it
can become excessive as in the context of idiopathic inflammatory intestinal disease as well as
enteric bacterial infection. In particular, occurrence and severity of colitis appears to be correlated
with the extent of neutrophil transmigration across the colonic epithelium and recent studies have
shown that neutrophil migration can incite the migration of other cells that mediate inflammation.
Thus, neutrophil transepithelial migration and accumulation at mucosal surfaces is a hallmark of
many inflammatory conditions, and this process correlates directly with clinical disease activity
and epithelial injury. Currently, the mechanisms that define neutrophil-epithelial interactions
during an inflammatory response are not completely understood. To fill this gap in knowledge, we
have uniquely shown that secretion of the eicosanoid hepoxilin A3 (HxA3) through the apically
expressed efflux pump known as MRP-2 establishes the chemotactic gradient across the
intestinal epithelium that is required for neutrophils from the submucosal space to move into the
colonic lumen at times of inflammation. Additionally, we identified the N-acyl ethanolamine (NAE)
class of eCBs to function in suppressing neutrophil transepithelial migration, and that these
molecules are secreted through the apical efflux pump known as P-glycoprotein (P-gp). We
hypothesize that these pro- and anti-inflammatory pathways communicate to provide a
responsive, integrated mechanism to control inflammation status and that these are dysregulated
in disease settings. To test this central hypothesis, we aim to identify the HxA3 receptor(s) on the
cell surface of neutrophils (Aim 1), determine the nature of NAE-type ECBs/P-gp and HxA3/MRP2
signaling (Aim 2), and to explore crosstalk points between these two pathways that drive the
inflammatory function of neutrophils (Aim 3). Successful completion of these Aims will provide a
consolidated picture of mechanisms controlling neutrophil transmigration across the intestinal
epithelium that will lead to both novel biological principles and therapeutic intervention strategies.

## Key facts

- **NIH application ID:** 10121794
- **Project number:** 2R01DK109677-04A1
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Beth A McCormick
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $617,407
- **Award type:** 2
- **Project period:** 2016-09-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10121794

## Citation

> US National Institutes of Health, RePORTER application 10121794, Control of Neutrophilic Inflammation in Intestinal Health and Disease (2R01DK109677-04A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10121794. Licensed CC0.

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