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.

Public Health Relevance

Myeloid cells, including macrophages, dendritic cells and microglia, comprise the majority of the immune cells that accumulate in the central nervous system (CNS) during Multiple Sclerosis (MS), and have been implicated in both damage and repair. In this proposal we will investigate the diversity, plasticity, biological properties and function of CNS myeloid cells during exacerbations and remissions of a widely used animal model of MS. We will also characterize myeloid cell subsets in postmortem MS tissue. This research may lead to the identification of novel myeloid biomarkers and therapeutic targets for the management of individuals with relapsing and progressive forms of MS who do not respond to currently available treatments.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Utz, Ursula
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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Giles, David A; Washnock-Schmid, Jesse M; Duncker, Patrick C et al. (2018) Myeloid cell plasticity in the evolution of central nervous system autoimmunity. Ann Neurol 83:131-141
Duncker, Patrick C; Stoolman, Joshua S; Huber, Amanda K et al. (2018) GM-CSF Promotes Chronic Disability in Experimental Autoimmune Encephalomyelitis by Altering the Composition of Central Nervous System-Infiltrating Cells, but Is Dispensable for Disease Induction. J Immunol 200:966-973
Stoolman, Joshua S; Duncker, Patrick C; Huber, Amanda K et al. (2018) An IFN?/CXCL2 regulatory pathway determines lesion localization during EAE. J Neuroinflammation 15:208