Arginase 1- expressing myeloid cells regulate Th17- mediated EAE
ECTRIMS Online Library. Atkinson J. 09/13/19; 279541; 279
Jeffrey Atkinson
Jeffrey Atkinson
Contributions
Abstract

Abstract: 279

Type: Scientific Session

Abstract Category: Pathology and pathogenesis of MS - Experimental models

J. Atkinson, B. Segal

Neurology, The Ohio State University Wexner Medical Center, Columbus, OH, United States

Introduction: 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 that express AAMC markers are dominant in the quiescent core, as opposed to the active demyelinating rim, of MS lesions.
Objective: To determine whether AAMC play a role in the resolution of inflammation and recovery of neurological function in a relapse-remitting model of EAE.
Methods: 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 chimeric mice by the adoptive transfer of purified myelin-reactive CD4+ TH17 cells and serially injected with either DT or vehicle. At peak EAE, CNS infiltrates were analyzed in representative mice from each group via flow cytometry.
Results: Depletion of Arg1+ inflammatory cells in Arg1-hDTR→WT chimeric mice exacerbated clinical EAE, and resulted in a high mortality rate compared with hDTR treated WT→WT, or vehicle treated Arg1-hDTR →WT, controls. The more severe clinical course was associated with a reduction in the absolute number of inflammatory cells present in the spinal cord at peak disease. Conversely, targeted depletion of Arg1 in immune cells had no impact on EAE incidence or severity.
Conclusions: 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.
Disclosure: Dr. Benjamin Segal and Dr. Jeffrey Atkinson have no conflicts of interest to disclose

Abstract: 279

Type: Scientific Session

Abstract Category: Pathology and pathogenesis of MS - Experimental models

J. Atkinson, B. Segal

Neurology, The Ohio State University Wexner Medical Center, Columbus, OH, United States

Introduction: 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 that express AAMC markers are dominant in the quiescent core, as opposed to the active demyelinating rim, of MS lesions.
Objective: To determine whether AAMC play a role in the resolution of inflammation and recovery of neurological function in a relapse-remitting model of EAE.
Methods: 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 chimeric mice by the adoptive transfer of purified myelin-reactive CD4+ TH17 cells and serially injected with either DT or vehicle. At peak EAE, CNS infiltrates were analyzed in representative mice from each group via flow cytometry.
Results: Depletion of Arg1+ inflammatory cells in Arg1-hDTR→WT chimeric mice exacerbated clinical EAE, and resulted in a high mortality rate compared with hDTR treated WT→WT, or vehicle treated Arg1-hDTR →WT, controls. The more severe clinical course was associated with a reduction in the absolute number of inflammatory cells present in the spinal cord at peak disease. Conversely, targeted depletion of Arg1 in immune cells had no impact on EAE incidence or severity.
Conclusions: 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.
Disclosure: Dr. Benjamin Segal and Dr. Jeffrey Atkinson have no conflicts of interest to disclose

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