Chronic TLR7 and TLR9 signaling drives anemia via differentiation of specialized hemophagocytes.

Abstract

Cytopenias are an important clinical problem associated with inflammatory disease and infection. We show that specialized phagocytes that internalize red blood cells develop in Toll-like receptor 7 (TLR7)-driven inflammation. TLR7 signaling caused the development of inflammatory hemophagocytes (iHPCs), which resemble splenic red pulp macrophages but are a distinct population derived from Ly6Chi monocytes. iHPCs were responsible for anemia and thrombocytopenia in TLR7-overexpressing mice, which have a macrophage activation syndrome (MAS)-like disease. Interferon regulatory factor 5 (IRF5), associated with MAS, participated in TLR7-driven iHPC differentiation. We also found iHPCs during experimental malarial anemia, in which they required endosomal TLR and MyD88 signaling for differentiation. Our findings uncover a mechanism by which TLR7 and TLR9 specify monocyte fate and identify a specialized population of phagocytes responsible for anemia and thrombocytopenia associated with inflammation and infection.

• Authors: Holly M Akilesh, Matthew B Buechler, Jeffrey M Duggan, William O Hahn, Bharati Matta, Xizhang Sun, Griffin Gessay, Elizabeth Whalen, Michael Mason, Scott R Presnell, Keith B Elkon, Adam Lacy-Hulbert, Betsy J Barnes, Marion Pepper, Jessica A Hamerman
• Journal: Science (New York, N.Y.) (Science) Vol. 363 Issue 6423 (01 11 2019) ISSN: 1095-9203 [Electronic] United States
• PMID: 30630901 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• DNA-Binding Proteins
• Interferon Regulatory Factors
• Irf5 protein, mouse
• Membrane Glycoproteins
• Myd88 protein, mouse
• Myeloid Differentiation Factor 88
• Spic protein, mouse
• Tlr7 protein, mouse
• Tlr9 protein, mouse
• Toll-Like Receptor 7
• Toll-Like Receptor 9

Topics

• Anemia (physiopathology)
• Animals
• Cell Differentiation
• Cells, Cultured
• DNA-Binding Proteins (physiology)
• Inflammation (physiopathology)
• Interferon Regulatory Factors (physiology)
• Macrophage Activation Syndrome (physiopathology)
• Membrane Glycoproteins (physiology)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Knockout
• Monocytes (cytology)
• Myeloid Differentiation Factor 88 (physiology)
• Phagocytes (cytology)
• Plasmodium yoelii
• Signal Transduction
• Spleen (cytology)
• Thrombocytopenia (physiopathology)
• Toll-Like Receptor 7 (physiology)
• Toll-Like Receptor 9 (physiology)
• Transcriptome