Komai Kyoko, Shichita Takashi, Ito Minako, Kanamori Mitsuhiro, Chikuma Shunsuke, Yoshimura Akihiko
Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Int Immunol. 2017 Feb 1;29(2):59-70. doi: 10.1093/intimm/dxx010.
Damage-associated molecular patterns (DAMPs) have been implicated in sterile inflammation in various tissue injuries. High-mobility group box 1 (HMGB1) is a representative DAMP, and has been shown to transmit signals through receptors for advanced glycation end products (RAGEs) and TLRs, including TLR2 and TLR4. HMGB1 does not, however, bind to TLRs with high affinity; therefore, the mechanism of HMGB1-mediated TLR activation remains unclear. In this study, we found that fluorescently labeled HMGB1 was efficiently internalized into macrophages through class A scavenger receptors. Although both M1- and M2-type macrophages internalized HMGB1, only M1-type macrophages secreted cytokines in response to HMGB1. The pan-class A scavenger receptor competitive inhibitor, maleylated bovine serum albumin (M-BSA), inhibited HMGB1 internalization and reduced cytokine production from macrophages in response to HMGB1 but not to LPS. The C-terminal acidic domain of HMGB1 is responsible for scavenger receptor-mediated internalization and cytokine production. HMGB1 and TLR4 co-localized in macrophages, and this interaction was disrupted by M-BSA, suggesting that class A scavenger receptors function as co-receptors of HMGB1 for TLR activation. M-BSA ameliorated LPS-induced sepsis and dextran sulfate sodium (DSS)-induced colitis models in which HMGB1 has been shown to play progressive roles. These data suggest that scavenger receptors function as co-receptors along with TLRs for HMGB1 in M1-type inflammatory macrophages.
损伤相关分子模式（DAMPs）与多种组织损伤中的无菌性炎症有关。高迁移率族蛋白B1（HMGB1）是一种代表性的DAMP，已被证明可通过晚期糖基化终产物受体（RAGEs）和Toll样受体（TLRs）传递信号，包括TLR2和TLR4。然而，HMGB1并不以高亲和力与TLRs结合；因此，HMGB1介导的TLR激活机制仍不清楚。在本研究中，我们发现荧光标记的HMGB1通过A类清道夫受体有效地内化到巨噬细胞中。虽然M1型和M2型巨噬细胞都能内化HMGB1，但只有M1型巨噬细胞对HMGB1有反应而分泌细胞因子。A类清道夫受体的泛竞争性抑制剂马来酰化牛血清白蛋白（M-BSA）抑制HMGB1的内化，并减少巨噬细胞对HMGB1而非LPS的细胞因子产生。HMGB1的C末端酸性结构域负责清道夫受体介导的内化和细胞因子产生。HMGB1和TLR4在巨噬细胞中共定位，这种相互作用被M-BSA破坏，表明A类清道夫受体作为HMGB1激活TLR的共受体发挥作用。M-BSA改善了LPS诱导的脓毒症模型和硫酸葡聚糖钠（DSS）诱导的结肠炎模型，在这些模型中HMGB1已被证明发挥着促进作用。这些数据表明，在M1型炎性巨噬细胞中，清道夫受体与TLRs一起作为HMGB1的共受体发挥作用。
