# Arginase-1 and iNOS expressing CNS myeloid cell subsets in EAE and MS

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2020 · $357,525

## Abstract

Multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS), is the
most common cause of non-traumatic neurological disability in young adults in the Western
Hemisphere. Significant progress has been made in the development of disease modifying therapies (DMT)
that decrease the frequency of clinical MS relapses by blocking or depleting pathogenic
lymphocytes. However, none of the approved DMT are curative, and none are effective in all patients. There
are no treatments that slow, or reverse, progressive forms of MS. The current proposal is based on the
contention that myeloid cells, and the factors that modulate them, should be considered as candidate
therapeutic targets for the treatment of relapsing or progressive forms of MS that are unresponsive to currently
used DMT. Myeloid cells (including macrophages, dendritic cells and microglia) comprise a major component
of the neuroinflammatory infiltrates in patients with MS and in mice with experimental autoimmune
encephalomyelitis (EAE, widely used as an animal model of MS). Abnormalities of myeloid cells have been
documented in relapsing-remitting as well as progressive forms of MS. The overall goal of this proposal is to
investigate the characteristics of the myeloid cells that accumulate in the central nervous system (CNS) during
different stages of autoimmune demyelinating disease. Bone marrow derived macrophages have been broadly
classified as pro-inflammatory M1 cells that express inducible nitric synthase (iNOS), and reparative M2 cells
that express arginase-1 (Arg1). Our preliminary studies show that the phenotypes of CNS-infiltrating myeloid
cells evolve with the progression and remission of EAE. During the preclinical stage, a significant percentage
of CNS myeloid cells express iNOS, but none express Arg1. At clinical onset, iNOS+Arg1+ double positive and
Arg1+ single positive myeloid cells appear in CNS infiltrates. As mice enter the remission phase only Arg1+
single positive myeloid cells remain. In Aim 1 we will use a panel of genetically engineered mice to elucidate
the pathways that drive iNOS+ versus Arg1+ myeloid cell polarization in the inflamed CNS during EAE. In Aims
2 and 3 we will characterize the transcriptomes and biological properties of the CNS-infiltrating myeloid
subsets, and determine the clinical and pathological consequences of depleting, skewing or blocking the
functions of Arg1+ or iNOS+ CNS myeloid cells, respectively. In Aim 4 we will investigate the density and
distribution of myeloid cell subsets in a panel of active, chronic active and relapsing MS lesions in autopsied
human brain sections. We are hopeful that this research will ultimately lead to the development of novel MS
therapies that suppress pathogenic myeloid subsets, while enhancing reparative subsets, with the goal of
mitigating, and even reversing, disability in individuals with relapsing-remitting and progressive forms of MS.

## Key facts

- **NIH application ID:** 9967165
- **Project number:** 5R01NS105385-04
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Benjamin M Segal
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $357,525
- **Award type:** 5
- **Project period:** 2019-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9967165

## Citation

> US National Institutes of Health, RePORTER application 9967165, Arginase-1 and iNOS expressing CNS myeloid cell subsets in EAE and MS (5R01NS105385-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9967165. Licensed CC0.

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