# Exploring the therapeutic mechanisms of proinflammatory myelin-laden macrophages retention in the injured spinal lesion core

> **NIH NIH R01** · FLORIDA STATE UNIVERSITY · 2023 · $378,918

## Abstract

PROJECT SUMMARY
Spinal cord injury (SCI) progression can be divided into acute and chronic phases. Following the primary injury,
bone marrow-derived macrophages (BMDMɸ) infiltrate to the injured epicenter where they engulf myelin debris
to become proinflammatory myelin-laden macrophages (Mye-Mϕ). Mye-Mɸ accumulate in the injured core
densely and occupy almost entire epicenter of injured area indefinitely, which would consequently result in: 1)
They prevent the entry and growth of axons, which inhibits remyelination. 2) They lose their normal phagocytic
capacity for dead cells and cellular debris, which may exacerbate the inflammatory microenvironment. 3) They
release inflammatory mediators, which trigger an inflammatory cascade that prevents tissue regeneration. Our
data indicated that the migratory potential of BMDMɸ is directly suppressed when they engulf myelin debris. We
resently reported that newly formed microvessels and their lining endothelial cells (ECs) in the injured cord are
able to engulf myelin debris. Myelin debris engulfment by ECs (Mye-ECs) significantly increased deposition of
extracellular matrices (ECM) such as collagen and fibronectin which may serve as extrinsic factor to promote
the adhesive interaction between Mye-Mϕ-ECs and lead to Mye-Mϕ retention in the injured lesion. Our central
hypothesis is that Mye-Mϕ retention in the injured core is mediated by intrinsic and extrinsic mechanisms which
promote Mye-Mɸ retention through ECM adhesion. The objective of the proposed project is to investigate the
underlying mechanisms of Mye-Mϕ sequestration and identify treatment strategies that target Mye-Mɸ in the
injury site, which may restore normal Mφ functions and lead to improvements in lesion resolution. The rationale
for the proposed research is based on preliminary investigations that demonstrate Mye-Mɸ become ‘trapped’ via
a mix of intrinsic (Mɸ produced) and extrinsic (environmental) mechanisms within the lesion. Our central
hypothesis will be tested in the following specific aims: 1) To study whether myelin debris, either directly or via
autocrine pathways, inhibits BMDMϕ migration ability which promotes their lesion retention; 2) To determine
whether adhesive ECM produced by Mye-ECs in the injured core aggravates Mye-Mɸ retention; and 3) To
investigate whether targeting Mye-Mφ and subsequently switching their phenotype toward a reparative
phenotype promotes tissue healing. This research is innovative because we propose that inflammatory Mye-
Mɸ trapped within the injured spinal cord lesion contribute to the chronic SCI lesion, preventing full resolution of
the injury. This work is significant because Aims 1 and 2 will identify the underlying mechanisms governing
Mye-Mφ retention, while Aim 3 will demonstrate novel strategies for the resolution of chronic SCI inflammation
and lesions. This will have the positive impact of identifying novel therapeutic strategies for therapeutic
interventions not only to treat SCI but also t...

## Key facts

- **NIH application ID:** 10569068
- **Project number:** 5R01NS126468-02
- **Recipient organization:** FLORIDA STATE UNIVERSITY
- **Principal Investigator:** Yi Ren
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $378,918
- **Award type:** 5
- **Project period:** 2022-02-15 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10569068

## Citation

> US National Institutes of Health, RePORTER application 10569068, Exploring the therapeutic mechanisms of proinflammatory myelin-laden macrophages retention in the injured spinal lesion core (5R01NS126468-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10569068. Licensed CC0.

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