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

作者：Zhuang Haoyang; Han Shuhong; Xu Yuan; Li Yi; Wang Hai; Yang Li Jun^*; Reeves Westley H

来源：Arthritis & Rheumatology, 2014, 66(1): 140-151.

DOI：10.1002/art.38189

Objective. To define the pathogenesis of bone marrow (BM) involvement in systemic lupus erythematosus (SLE).
Methods. Tumor necrosis factor alpha (TNF alpha) 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), TNF alpha(-/-), Toll-like receptor-deficient (TLR-7(-/-)), interferon (IFN)-alpha/beta/omega receptor-knockout (IFNAR alpha(-/-)), and B cell-deficient (mu mt) mice treated with pristane. Flow cytometry was used to examine TNF alpha production (by intracellular staining) and plasma cell/plasmablast development. CXCL12 expression was determined by quantitative polymerase chain reaction.
Results. BM from SLE patients exhibited striking death of niche and hematopoietic cells associated with TNF alpha overproduction. BM from mice with a type I IFN-mediated lupus syndrome induced by pristane showed similar abnormalities. TNF alpha was produced mainly by BM neutrophils, many with phagocytosed nuclear material (lupus erythematosus cells). TNF alpha production was abolished in pristane-treated TLR-7(-/-) and mu mt mice but was restored in mu mt 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 TNF alpha(-/-) 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 TN alpha(-/-). mice.
Conclusion. Although autoantibodies and glomerulonephritis are type I IFN dependent, lupus-associated BM abnormalities were TLR-7 and TNF alpha 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 TNF alpha production mediating glomerulonephritis and hematologic involvement, respectively.

• 出版日期2014-1