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Molecular chaperoning by glucose‐regulated protein 170 in the extracellular milieu promotes macrophage‐mediated pathogen sensing and innate immunity
Author(s) -
Zuo Daming,
Yu Xiaofei,
Guo Chunqing,
Yi Huanfa,
Chen Xing,
Conrad Daniel H.,
Guo Tai L.,
Chen Zhengliang,
Fisher Paul B.,
Subjeck John R.,
Wang XiangYang
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.11-197707
Subject(s) - innate immune system , tlr9 , microbiology and biotechnology , biology , pathogen associated molecular pattern , proinflammatory cytokine , extracellular , intracellular , receptor , cpg oligodeoxynucleotide , internalization , pattern recognition receptor , inflammation , immunology , biochemistry , dna methylation , gene expression , gene
Recognition of pathogen‐associated molecular patterns by innate immune receptors is essential for host defense responses. Although extracellular stress proteins are considered as indicators of the stressful conditions ( e.g. , infection or cell injury), the exact roles of these molecules in the extracellular milieu remain less defined. We found that glucose‐regulated protein 170 (Grp170), the largest stress protein and molecular chaperone, is highly efficient in binding CpG oligodeoxynucleotides (CpG‐ODN), the microbial DNA mimetic sensed by toll‐like receptor 9 (TLR9). Extracellular Grp170 markedly potentiates the endocytosis and internalization of CpG‐ODN by mouse bone marrow‐derived macrophages and directly interacts with endosomal TLR9 on cell entry. These molecular collaborations result in the synergistic activation of the MyD88‐dependent signaling and enhanced production of proinflammatory cytokines and nitric oxide in mouse primary macrophages as well as human THP‐1 monocyte‐derived macrophages, suggesting that Grp170 released from injured cells facilitates the sensing of pathogen‐associated “danger” signals by intracellular receptors. This CpG‐ODN chaperone complex‐promoted innate immunity confers increased resistance in mice to infection of Listeria monocytogenes compared with CpG‐ODN treatment alone. Our studies reveal a previously unrecognized attribute of Grp170 as a superior DNA‐binding chaperone capable of amplifying TLR9 activation on pathogen recognition, which provides a conceptual advance in understanding the dynamics of ancient chaperoning functions inside and outside the cell.—Zuo, D., Yu, X., Guo, C., Yi, H., Chen, X., Conrad, D. H., Guo, T. L., Chen, Z., Fisher, P. B., Subjeck, J. R., Wang, X.‐Y. Molecular chaperoning by glucose‐regulated protein 170 in the extracellular milieu promotes macrophage‐mediated pathogen sensing and innate immunity. FASEB J. 26, 1493‐1505 (2012). www.fasebj.org