Antibody neutralization of microbiota-derived circulating peptidoglycan dampens inflammation and ameliorates autoimmunity

被引:76
作者
Huang, Zhenxing [1 ]
Wang, Jianhe [1 ,2 ]
Xu, Xiaoli [1 ]
Wang, Haishan [1 ]
Qiao, Yuan [1 ]
Chu, Wern Cui [1 ]
Xu, Shengli [3 ]
Chai, Louis [4 ,5 ,6 ]
Cottier, Fabien [7 ]
Pavelka, Norman [7 ]
Oosting, Marije [8 ]
Joosten, Leo A. B. [8 ]
Netea, Mihai [8 ]
Ng, Carol Yee Leng [9 ]
Leong, Khai Pang [10 ]
Kundu, Parag [11 ,12 ]
Lam, Kong-Peng [3 ]
Pettersson, Sven [11 ,12 ,13 ]
Wang, Yue [1 ,14 ]
机构
[1] Agcy Sci Technol & Res, Inst Mol & Cell Biol, Singapore, Singapore
[2] South China Agr Univ, Integrat Microbiol Res Ctr, Guangzhou, Guangdong, Peoples R China
[3] Agcy Sci Technol & Res, Bioproc Technol Inst, Singapore, Singapore
[4] Natl Univ Hlth Syst, Univ Med Cluster, Div Infect Dis, Singapore, Singapore
[5] Natl Univ Canc Inst, Dept Haematol Oncol, Singapore, Singapore
[6] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Med, Singapore, Singapore
[7] Agcy Sci Technol & Res, Singapore Immunol Network, Singapore, Singapore
[8] Radboud Univ Nijmegen, Med Ctr, Dept Internal Med, Nijmegen, Netherlands
[9] Tan Tock Seng Hosp, Clin Immunol Lab, Singapore, Singapore
[10] Tan Tock Seng Hosp, Allergy & Immunol Lab, Dept Rheumatol, Singapore, Singapore
[11] Nanyang Technol Univ, Lee Kong Chian Sch Med, Singapore, Singapore
[12] Nanyang Technol Univ, Singapore Ctr Environm Life Sci Engn, Singapore, Singapore
[13] Karolinska Inst, Care Sci & Soc, Dept Neurobiol, Stockholm, Sweden
[14] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Biochem, Singapore, Singapore
基金
英国医学研究理事会;
关键词
GUT MICROBIOTA; NOD1; ADJUVANT; INNATE; WALL;
D O I
10.1038/s41564-019-0381-1
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
The human microbiota provides tonic signals that calibrate the host immune response(1,2), but their identity is unknown. Bacterial peptidoglycan (PGN) subunits are likely candidates since they are well-known immunity-enhancing adjuvants, released by most bacteria during growth, and have been found in the blood of healthy people(3-7). We developed a monoclonal antibody (mAb), 2E7, that targets muramyl-L-alanyl-D-isoglutamine (MDP), a conserved and minimal immunostimulatory structure of PGN. Using 2E7-based assays, we detected PGN ubiquitously in human blood at a broad range of concentrations that is relatively stable in each individual. We also detected PGN in the serum of several warm-blooded animals. However, PGN is barely detectable in the serum of germfree mice, indicating that its origin is the host microbiota. Neutralization of circulating PGN via intraperitoneal administration of 2E7 suppressed the development of autoimmune arthritis and experimental autoimmune encephalomyelitis in mice. Arthritic NOD2(-/-) mice lacking the MDP sensor did not respond to 2E7, indicating that 2E7 dampens inflammation by blocking nucleotide-binding oligomerization domain-containing protein 2 (NOD2)-mediated pathways. We propose that circulating PGN acts as a natural immune potentiator that tunes the host immune response; altering its level is a promising therapeutic strategy for immune-mediated diseases.
引用
收藏
页码:766 / 773
页数:8
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