Abstract
In multiple sclerosis and the experimental autoimmune encephalitis (EAE) mouse model, two pools of morphologically indistinguishable phagocytic cells, microglia and inflammatory macrophages, accrue from proliferating resident precursors and recruitment of blood-borne progenitors, respectively. Whether these cell types are functionally equivalent is hotly debated, but is challenging to address experimentally. Using a combination of parabiosis and myeloablation to replace circulating progenitors without affecting CNS-resident microglia, we found a strong correlation between monocyte infiltration and progression to the paralytic stage of EAE. Inhibition of chemokine receptor-dependent recruitment of monocytes to the CNS blocked EAE progression, suggesting that these infiltrating cells are essential for pathogenesis. Finally, we found that, although microglia can enter the cell cycle and return to quiescence following remission, recruited monocytes vanish, and therefore do not ultimately contribute to the resident microglial pool. In conclusion, we identified two distinct subsets of myelomonocytic cells with distinct roles in neuroinflammation and disease progression.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bone Marrow Transplantation / methods
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Bromodeoxyuridine / metabolism
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CD11b Antigen / metabolism
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Calcium-Binding Proteins / metabolism
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Chemotaxis, Leukocyte / physiology*
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Disease Models, Animal
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Disease Progression*
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Encephalomyelitis, Autoimmune, Experimental / etiology
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Encephalomyelitis, Autoimmune, Experimental / pathology*
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Encephalomyelitis, Autoimmune, Experimental / prevention & control
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Encephalomyelitis, Autoimmune, Experimental / surgery
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Female
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Flow Cytometry
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Green Fluorescent Proteins / genetics
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Inflammation / therapy
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Macrophages / physiology
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Microfilament Proteins / metabolism
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Microglia / physiology*
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Monocytes / physiology*
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Myeloablative Agonists / adverse effects
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Parabiosis / methods
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Receptors, CCR2 / deficiency
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Receptors, Interleukin-8A / genetics
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Severity of Illness Index
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Time Factors
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Whole-Body Irradiation / adverse effects
Substances
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Aif1 protein, mouse
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CD11b Antigen
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CXCR1-like protein, mouse
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Calcium-Binding Proteins
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Ccr2 protein, mouse
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Microfilament Proteins
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Myeloablative Agonists
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Receptors, CCR2
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Receptors, Interleukin-8A
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Green Fluorescent Proteins
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Bromodeoxyuridine