Pathogenesis – Immunology Oral Presentation

PS02.03 - Targeted Depletion of Alternatively-Activated Myeloid Cells Exacerbates Adoptive Transfer EAE

  • J. Atkinson
  • J. Atkinson
  • B. Segal
Presentation Number
Presentation Topic
Pathogenesis – Immunology
Lecture Time
10:45 - 10:57



A significant proportion of the inflammatory cells that infiltrate the central nervous system (CNS) of patients with multiple sclerosis (MS) and animals with experimental autoimmune encephalomyelitis (EAE), are myeloid cells, including monocyte-derived macrophages and dendritic cells. A large body of literature supports a pathogenic role of these subsets during the acute phase of CNS demyelinating lesion formation. However, we and others have shown that CNS-infiltrating myeloid cells are more heterogeneous than traditionally thought, and that their phenotype evolves during the clinical course. Arginase 1 (Arg1) is an inhibitor of nitric oxide (NO) and a canonical marker of alternatively activated myeloid cells (AAMC) with anti-inflammatory properties. Arg1+ myeloid cells accumulate in the CNS from peak EAE through remission, but are not detectable in the blood or peripheral tissues. Furthermore, myeloid cells expressing AAMC markers are dominant in the quiescent core, as opposed to the active demyelinating rim, of MS lesions.


The objective of this study is to determine the role of AAMCs in the resolution of inflammation and recovery of neurological function in a relapsing-remitting model of EAE.


To address that hypothesis, we constructed a transgenic mouse strain with the human diphtheria toxin receptor (hDTR) gene (Hbegf) linked to the Arg1 promoter (Arg1-hDTR mice). In order to restrict hDTR expression to hematopoietic cells we reconstituted lethally irradiated WT mice with bone marrow cells from Arg1-hDTR donors. EAE was induced in Arg1-hDTR→WT and WT→WT chimeric mice by the adoptive transfer of purified myelin-reactive CD4+ TH17 cells and treated with diphtheria toxin (DT). CNS inflammatory cell composition was evaluated via flow cytometry and cell subsets were isolated via FACS for transcriptional analysis.


Depletion of Arg1+ inflammatory cells in Arg1-hDTR→WT chimeric mice exacerbated EAE induced by the transfer of encephalitogenic TH17 cells, and resulted in a high mortality rate compared with PBS-treatment and WT→WT controls. Monocyte-derived dendritic cells (mDC) possessing an anti-inflammatory phenotype were most susceptible to depletion. The more severe clinical course observed following depletion was associated with an increase in the absolute number of Arg1- inflammatory macrophages present in the spinal cord at peak disease, coincident with elevated levels of proinflammatory cytokines and chemokines in spinal cord homogenates. Conversely, targeted depletion of Arg1 in immune cells had no impact on EAE incidence or severity.


This study suggests that CNS accumulation of AAMC during later stages of autoimmune demyelinating disease suppresses the local inflammatory response and ameliorates neurological deficits by an Arg1- independent mechanism.