Abstract
Mice overexpressing TLR7 (TLR7.1 mice) are a model of systemic lupus erythematosus pathogenesis and exhibit peripheral myeloid expansion. We show that TLR7.1 mice have a dramatic expansion of splenic cells that derive from granulocyte/macrophage progenitors (GMP) compared with wild-type mice. In the bone marrow, TLR7.1 mice exhibited hallmarks of emergency myelopoiesis and contained a discrete population of Sca-1(+) GMP, termed emergency GMP, which are more proliferative and superior myeloid precursors than classical Sca-1(-) GMP. The emergency myelopoiesis and peripheral myeloid expansion in TLR7.1 mice was dependent on type I IFN signaling. TLR7 agonist administration to nontransgenic mice also drove type I IFN-dependent emergency myelopoiesis. TLR7.1 plasmacytoid dendritic cells were cell-intrinsically activated by TLR7 overexpression and constitutively produced type I IFN mRNA. This study shows that type I IFN can act upon myeloid progenitors to promote the development of emergency GMP, which leads to an expansion of their progeny in the periphery.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Antigens, Ly / analysis
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Bone Marrow / pathology
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Cell Division
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Cell Lineage
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Dendritic Cells / immunology
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Disease Models, Animal
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Gene Expression Regulation / immunology
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Granulocytes / pathology
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Interferon Type I / biosynthesis
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Interferon Type I / genetics
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Interferon Type I / physiology*
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Lupus Erythematosus, Systemic / immunology
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Lupus Erythematosus, Systemic / pathology
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Macrophages / pathology
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Membrane Glycoproteins / agonists
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Membrane Glycoproteins / biosynthesis
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / physiology*
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Membrane Proteins / analysis
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Mice
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Mice, Transgenic
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Models, Immunological
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Myeloid Cells / pathology
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Myelopoiesis / physiology*
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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Radiation Chimera
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Receptor, Interferon alpha-beta / deficiency
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Signal Transduction / physiology
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Spleen / pathology
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Toll-Like Receptor 7 / agonists
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Toll-Like Receptor 7 / biosynthesis
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Toll-Like Receptor 7 / genetics
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Toll-Like Receptor 7 / physiology*
Substances
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Antigens, Ly
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Ifnar1 protein, mouse
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Interferon Type I
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Ly6a protein, mouse
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Membrane Glycoproteins
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Membrane Proteins
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RNA, Messenger
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Tlr7 protein, mouse
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Toll-Like Receptor 7
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Receptor, Interferon alpha-beta