Jiangsu Provincial Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Science, Soochow University, Suzhou 215123, People's Republic of China.
Jiangsu Provincial Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Science, Soochow University, Suzhou 215123, People's Republic of China.
Biochim Biophys Acta Mol Basis Dis. 2021 Oct 1;1867(10):166184. doi: 10.1016/j.bbadis.2021.166184. Epub 2021 Jun 1.
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with unclear pathogenesis. We previously reported that syngenetic, activated lymphocyte-derived DNA (ALD-DNA) could robustly elicit macrophage activation, which plays an important role in the pathogenesis of murine lupus nephritis. In addition, extracellular HMGB1 obviously facilitated the accumulation of ALD-DNA in endosomes and promoted macrophage inflammation. While the detailed mechanism was still unknown. In this study, we found that HMGB1 could obviously change the DNA uptake pathways in macrophages. ALD-DNA alone was mainly uptake by the low efficient and unselective macropinocytosis, while extracellular HMGB1 potently promoted the more efficient and specific clathrin-/caveolin-1-dependent receptor-mediated endocytosis pathways, and led to the rapid and abundant aggregation of ALD-DNA in endosomes. This effect relied on the DNA binding ability and TLR2/TLR4 of HMGB1. Our study not only helped us to understand the promotion mechanisms of extracellular HMGB1 on ALD-DNA-induced macrophage inflammation, but also provided some clues to the pathogenesis of SLE.
系统性红斑狼疮（SLE）是一种病因不明的慢性自身免疫性疾病。我们之前曾报道过，同基因激活的淋巴细胞衍生 DNA（ALD-DNA）可以强烈引发巨噬细胞活化，这在狼疮性肾炎的发病机制中起着重要作用。此外，细胞外高迁移率族蛋白 B1（HMGB1）明显促进了 ALD-DNA 在内涵体中的积累，并促进了巨噬细胞炎症。虽然其详细机制尚不清楚。在这项研究中，我们发现 HMGB1 可以明显改变巨噬细胞中的 DNA 摄取途径。单独的 ALD-DNA 主要通过低效且非选择性的巨胞饮作用摄取，而细胞外 HMGB1 则有力地促进了更有效且特异性的网格蛋白/窖蛋白-1 依赖性受体介导的内吞作用途径，并导致 ALD-DNA 在内涵体中迅速且大量聚集。这种效应依赖于 HMGB1 的 DNA 结合能力和 TLR2/TLR4。我们的研究不仅有助于我们了解细胞外 HMGB1 对 ALD-DNA 诱导的巨噬细胞炎症的促进机制，而且为 SLE 的发病机制提供了一些线索。
