Toll-like Receptor 7–Stimulated Tumor Necrosis Factor α Causes Bone Marrow Damage in Systemic Lupus Erythematosus




To define the pathogenesis of bone marrow (BM) involvement in systemic lupus erythematosus (SLE).


Tumor necrosis factor α (TNFα) levels, cell death, and cellular damage in BM from SLE patients, controls, and mice with pristane-induced lupus were analyzed using a morphometric technique and immunohistochemistry. The pathogenesis of BM abnormalities was studied in wild-type (WT), TNFα−/−, Toll-like receptor–deficient (TLR-7−/−), interferon (IFN)–α/β/ω receptor–knockout (IFNAR−/−), and B cell–deficient (μmt) mice treated with pristane. Flow cytometry was used to examine TNFα production (by intracellular staining) and plasma cell/plasmablast development. CXCL12 expression was determined by quantitative polymerase chain reaction.


BM from SLE patients exhibited striking death of niche and hematopoietic cells associated with TNFα overproduction. BM from mice with a type I IFN–mediated lupus syndrome induced by pristane showed similar abnormalities. TNFα was produced mainly by BM neutrophils, many with phagocytosed nuclear material (lupus erythematosus cells). TNFα production was abolished in pristane-treated TLR-7−/− and μmt mice but was restored in μmt mice by infusing normal plasma. Pristane-treated WT and IFNAR−/− mice developed anemia, BM hypocellularity, and extramedullary hematopoiesis, which were absent in TLR-7−/− and TNFα−/− mice. Additionally, the expression of CXCL12, which is produced by stromal cells and mediates homing of hematopoietic cells and plasmablasts, was decreased in BM from pristane-treated WT mice but was normal in BM from pristane-treated TNFα−/− mice.


Although autoantibodies and glomerulonephritis are type I IFN dependent, lupus-associated BM abnormalities were TLR-7 and TNFα driven but type I IFN independent, suggesting that lupus is a disorder of innate immunity in which TLR-7 activation by phagocytosed nuclei causes relentless type I IFN and TNFα production mediating glomerulonephritis and hematologic involvement, respectively.