Role of scavenger receptors as damage-associated molecular pattern receptors in Toll-like receptor activation.
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.
Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Kyoko
K
Komai
Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Takashi
T
Shichita
Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Minako
M
Ito
Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Mitsuhiro
M
Kanamori
Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Shunsuke
S
Chikuma
Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Akihiko
A
Yoshimura
D000818:Animals; D002417:Cattle; D002454:Cell Differentiation; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D024243:HMGB1 Protein / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D051117:Scavenger Receptors, Class A / Q000235:genetics / Q000378:metabolism*; D018805:Sepsis / Q000139:chemically induced / Q000276:immunology*; D012710:Serum Albumin, Bovine / Q000008:administration & dosage; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism
D016207:Cytokines; D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; C092228:Marco protein, mouse; C495140:Msr1 protein, mouse; D011971:Receptors, Immunologic; D051117:Scavenger Receptors, Class A; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D012710:Serum Albumin, Bovine
DAMPs; TLR; colitis; endocytosis; macrophage