# Neutrophils instruct macrophage responses to promote mucosal healing

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2023 · $349,908

## Abstract

Project Summary/Abstract
Mucosal healing is considered an important clinical end-point of gastrointestinal disorders, including
inflammatory bowel diseases (IBD). As such, it is an attractive target for developing therapies aimed at achieving
sustained clinical remission. PMN presence in the intestinal mucosa is often associated with disease severity
and tissue damage, however, PMN contributions to resolution of inflammation are increasingly recognized. Thus,
while our view of PMNs as terminally differentiated phagocytes that promote tissue damage is changing,
mechanisms underlying beneficial roles of PMNs remain poorly understood. Likewise, although macrophage
(Mϕ) contributions to mounting immune responses in the gut and to resolution of inflammation are well
recognized, molecular cues that instruct their effector functions remain to be defined.
Our ongoing studies indicate a novel and beneficial contribution of tissue PMNs to the resolution of inflammation
and mucosal injury. We have identified several novel mechanisms and new molecular players by which PMNs
instruct the activity of inflammatory gut Mϕs to promote mucosal healing. We found that PMN extracellular
vesicles (EVs) mediate localized transfer of regulatory micro-RNAs (miRNAs) and pro-repair factors (e.g. TGF-
β1), which respectively, through parallel activity suppress inflammatory and promote pro-repair cytokine
expression in gut Mϕs. We also identified a new regulatory role for a well-characterized PMN adhesion ligand,
ICAM-1, in regulating Mϕ efferocytotic activity. ICAM-1 is highly upregulated during Mϕ activation (its expression
is restricted to inflammatory Mϕs) and when ligated by PMN binding, critically regulates clearance of
apoptotic/necrotic epithelial cells in injured tissue.
Therefore, the overall goal of this proposal is to test a novel concept whereby tissue infiltrating PMNs facilitate
reprogramming of gut Mϕs to promote inflammatory resolution of the injured intestinal mucosa.
Proposed experiments will use state of the art imaging techniques, powerful in vivo injury models combined with
innovative molecular and biochemical approaches to: 1. Determine how PMN-Mϕ interactions facilitate injury
resolution in the intestinal mucosa. 2. Determine how PMN-EVs enhance the pro-repair activity of inflammatory
wound Mϕs and 3. Determine how PMN binding and ICAM-1 signaling in wound Mϕs regulate efferocytosis and
facilitate wound debridement.
Our studies will define new mechanisms governing innate immune cell interactions in wounded mucosa and their
function in injury resolution.

## Key facts

- **NIH application ID:** 10611883
- **Project number:** 5R01DK124199-04
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Ronen Sumagin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $349,908
- **Award type:** 5
- **Project period:** 2020-05-05 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10611883

## Citation

> US National Institutes of Health, RePORTER application 10611883, Neutrophils instruct macrophage responses to promote mucosal healing (5R01DK124199-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10611883. Licensed CC0.

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