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

• Published in: Science (American Association for the Advancement of Science) Vol. 363; no. 6423
• Main Authors: Akilesh, Holly M, Buechler, Matthew B, Duggan, Jeffrey M, Hahn, William O, Matta, Bharati, Sun, Xizhang, Gessay, Griffin, Whalen, Elizabeth, Mason, Michael, Presnell, Scott R, Elkon, Keith B, Lacy-Hulbert, Adam, Barnes, Betsy J, Pepper, Marion, Hamerman, Jessica A
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 11.01.2019
• Subjects: Anemia; Anemia - physiopathology; Animals; Autoimmune diseases; Cell activation; Cell Differentiation; Cell surface; Cells, Cultured; Depletion; Differentiation; Disease; Disorders; DNA-Binding Proteins - physiology; Erythrocytes; Immune clearance; Immune system; In vivo methods and tests; Individualized Instruction; Infections; Infectious diseases; Inflammation; Inflammation - physiopathology; Inflammatory diseases; Innate immunity; Interferon; Interferon regulatory factor; Interferon Regulatory Factors - physiology; Interleukins; Leukocytes; Macrophage Activation Syndrome - physiopathology; Macrophages; Membrane Glycoproteins - physiology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Monocytes; Monocytes - cytology; MyD88 protein; Myeloid Differentiation Factor 88 - physiology; Nucleic acids; Pathogens; Pattern recognition; Phagocytes; Phagocytes - cytology; Phagocytosis; Phenotypes; Plasmodium yoelii; Platelets; Population; Proteins; Receptors; Red pulp; Signal Transduction; Signaling; Spleen; Spleen - cytology; Thrombocytopenia; Thrombocytopenia - physiopathology; TLR3 protein; Toll-Like Receptor 7 - physiology; Toll-Like Receptor 9 - physiology; Toll-like receptors; Transcriptome; Viral infections
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aao5213

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 Ly6C 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.