Extracellular HMGB1 augments macrophage inflammation by facilitating the endosomal accumulation of ALD-DNA via TLR2/4-mediated endocytosis

Biochim Biophys Acta Mol Basis Dis. 2021 Jun 1;1867(10):166184. doi: 10.1016/j.bbadis.2021.166184. Online ahead of print.

Abstract

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.

Keywords: ALD-DNA; Endocytosis; HMGB1; Macrophage inflammation; SLE.