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Abstract Number: 1431

Human TLR8 Leads to Fatal Anemia Due to Ineffective Erythropoiesis in Bone Marrow Erythroblastic Islands in Murine SLE

Naomi Maria1, Julien Papoin1, Chirag Raparia1, Zeguo Sun2, Shani Martinez1, Weijia Zhang2, Lionel Blanc1 and Anne Davidson1, 1Institute of Molecular Medicine, Feinstein Institutes for Medical Research, Manhasset, NY, 2Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY

Meeting: ACR Convergence 2021

Keywords: Erythropoiesis, Fatal anemia, innate immunity, Systemic lupus erythematosus (SLE), Toll Like receptors

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Session Information

Date: Monday, November 8, 2021

Session Title: Abstracts: Innate Immunity (1430–1433)

Session Type: Abstract Session

Session Time: 10:45AM-11:00AM

Background/Purpose: There are multiple causes of anemia in SLE including hemolysis, inflammation, renal insufficiency and, more rarely, microangiopathy, hemophagocytosis and bone marrow insufficiency. One cause of anemia in SLE is impaired bone marrow erythropoiesis, possibly mediated by inflammatory cytokines such as TNF or Type I interferon, or by autoantibodies. Because innate immune mechanisms are associated with anemia, here we studied the effect of TLR7 and TLR8 overexpression on SLE related anemia in an animal model in which we introduced human TLR8. Mouse and human TLR7 and human TLR8 recognize ssRNA but human TLR7 and TLR8 differ with respect to their cellular locations and the type of RNA they recognize.

Methods: Sle1.Yaa mice expressing 1-2 copies of huTLR8 as a BAC transgene (huTR8.tg) were generated and followed clinically. HuTLR8 DNA copy number and mRNA expression was confirmed by qDigital and qRT-PCR respectively. Serum autoantibodies were assessed over time. Spleen weights were assessed and splenocytes, renal and bone marrow cells were characterized by flow cytometric analysis. Mammalian erythropoiesis occurs within anatomic niches, erythroblastic islands (EBIs), where erythroblast maturation occurs by close interaction with a central macrophage. EBIs from both bone marrow and spleen were characterized by multispectral imaging flow cytometry and isolated for single cell RNA sequencing (scRNAseq) analysis.

Results: HuTLR8.tg SLE1.Yaa males expressing 2 copies of huTLR8 showed accelerated mortality by 4 months of age compared with >9 months in Sle1.Yaa and homozygous huTLR8.tg C57BL/6.Yaa controls. Complete blood counts in male SLE1.Yaa.huTLR8 mice identified severe anemia as the cause of death. This phenotype first became evident at >12 weeks of age, required both the Sle1 and Yaa loci, as well as the huTLR8 transgene and was more common and severe in huTLR8tg homozygotes. Flow cytometric analyses revealed ineffective erythropoiesis with a block at the transition from the CFU-E to proerythroblast stage. Single cell RNASeq showed that this was associated with an inflammatory phenotype in erythroblastic island central macrophages with a downregulation in adhesion and phagocytic receptors. Compensatory stress erythropoiesis in the spleen was associated with vast expansion of red pulp macrophages with phagocytic properties and fatal anemia was associated with a decrease in red blood cell (RBC) half-life, suggesting that excessive RBC phagocytosis eventually exceeds the capability of stress erythropoiesis to replace the RBC mass.

Conclusion: These data implicate huTLR8 innate inflammatory signals and the presence of auto-antibodies in defective bone marrow hematopoiesis, resulting in an altered phenotype of bone marrow EBI-associated central macrophages consequently reducing erythroid output. Furthermore, loss of mature cells through increased phagocytosis of red cells results in a fatal anemia phenotype. Further elucidating how dysregulated TLR8 signaling disrupts homeostasis of the bone marrow niche is crucial to better understand the role of this TLR in autoimmunity and will facilitate more precise therapeutic targeting.


Disclosures: N. Maria, None; J. Papoin, None; C. Raparia, None; Z. Sun, None; S. Martinez, None; W. Zhang, RenalytixAI, 1, 9; L. Blanc, None; A. Davidson, None.

To cite this abstract in AMA style:

Maria N, Papoin J, Raparia C, Sun Z, Martinez S, Zhang W, Blanc L, Davidson A. Human TLR8 Leads to Fatal Anemia Due to Ineffective Erythropoiesis in Bone Marrow Erythroblastic Islands in Murine SLE [abstract]. Arthritis Rheumatol. 2021; 73 (suppl 9). https://acrabstracts.org/abstract/human-tlr8-leads-to-fatal-anemia-due-to-ineffective-erythropoiesis-in-bone-marrow-erythroblastic-islands-in-murine-sle/. Accessed June 2, 2023.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/human-tlr8-leads-to-fatal-anemia-due-to-ineffective-erythropoiesis-in-bone-marrow-erythroblastic-islands-in-murine-sle/

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