Human TLR8 induces inflammatory bone marrow erythromyeloblastic islands and anemia in SLE-prone mice

Abstract

Anemia commonly occurs in systemic lupus erythematosus, a disease characterized by innate immune activation by nucleic acids. Overactivation of cytoplasmic sensors by self-DNA or RNA can cause erythroid cell death, while sparing other hematopoietic cell lineages. Whereas chronic inflammation is involved in this mechanism, less is known about the impact of systemic lupus erythematosus on the BM erythropoietic niche. We discovered that expression of the endosomal ssRNA sensor human TLR8 induces fatal anemia in Sle1.Yaa lupus mice. We observed that anemia was associated with a decrease in erythromyeloblastic islands and a block in differentiation at the CFU-E to proerythroblast transition in the BM. Single-cell RNAseq analyses of isolated BM erythromyeloblastic islands from human TLR8-expressing mice revealed that genes associated with essential central macrophage functions including adhesion and provision of nutrients were down-regulated. Although compensatory stress erythropoiesis occurred in the spleen, red blood cell half-life decreased because of hemophagocytosis. These data implicate the endosomal RNA sensor TLR8 as an additional innate receptor whose overactivation causes acquired failure of erythropoiesis via myeloid cell dysregulation.

Human and Murine Toll-like Receptor-Driven Disease in Systemic Lupus Erythematosus

“…Humanized mouse models of SLE involve transferring PBMC from SLE patients to immunodeficient mice or transferring human hematopoietic stems cells to immunodeficient mice with subsequent induction of lupus via intraperitoneal injection of pristane (reviewed in [85]). Other studies have introduced human genes into mice strains, like human TLR8 in an SLE1.Yaa strain that induced fatal anemia [86]. In a recent study by Cakan et al (2023) to study the role of TLR7 and TLR9 in induction of B-cell tolerance, they used NOD-scidcommon gamma chain (γc) knockout (NSG) immunodeficient mice with CD34 + human fetal hematopoietic stem cells (HSCs) transduced with GFP-tagged lentivirus expressing shRNA to inhibit the expression of MYD88, TLR7, and TLR9 [87].…”