Circulating Ly-6C+ myeloid precursors migrate to the CNS and play a pathogenic role during autoimmune demyelinating disease.
Mature myeloid cells (macrophages and CD11b(+) dendritic cells) form a prominent component of neuroinflammatory infiltrates in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). The mechanism by which these cells are replenished during relapsing and chronic neuroinflammation is poorly understood. Here we demonstrate that CD11b(+)CD62L(+)Ly6C(hi) monocytes with colony-forming potential are mobilized into the bloodstream by a granulocyte-macrophage colony-stimulating factor-dependent pathway immediately before EAE relapses. Circulating Ly6C(hi) monocytes traffic across the blood-brain barrier, up-regulate proinflammatory molecules, and differentiate into central nervous system dendritic cells and macrophages. Enrichment of Ly6C(hi) monocytes in the circulating pool is associated with an earlier onset and increased severity of clinical EAE. Our studies indicate that granulocyte-macrophage colony-stimulating factor-driven release of Ly6C(hi) precursors from the bone marrow prevents exhaustion of central nervous system myeloid populations during relapsing or chronic autoimmune demyelination, suggesting a novel pathway for therapeutic targeting.
King
Irah L
IL
Interdepartmental Graduate Program in Neuroscience, School of Medicine and Dentistry, University of Rochester, NY, USA.
Dickendesher
Travis L
TL
Segal
Benjamin M
BM
D000818:Animals; D000950:Antigens, Ly / Q000097:blood / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology*; D002490:Central Nervous System / Q000276:immunology / Q000473:pathology*; D002908:Chronic Disease; D020278:Demyelinating Autoimmune Diseases, CNS / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000502:physiology; D007249:Inflammation / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D023461:Myeloid Progenitor Cells / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D038042:Myelopoiesis / Q000235:genetics; D012008:Recurrence; D012720:Severity of Illness Index
D000950:Antigens, Ly; C494192:Ly-6C antigen, mouse; D016178:Granulocyte-Macrophage Colony-Stimulating Factor