CD16 Regulates TRIF-Dependent TLR4 Response in Human Monocytes and Their Subsets

被引:33
作者
Shalova, Irina N. [1 ]
Kajiji, Tasneem [1 ]
Lim, Jyue Yuan [1 ]
Gomez-Pina, Vanesa [2 ]
Fernandez-Ruiz, Irene [2 ]
Arnalich, Francisco [2 ]
Iau, Philip Tsau Choong [3 ]
Lopez-Collazo, Eduardo [2 ]
Wong, Siew-Cheng [1 ]
Biswas, Subhra K. [1 ]
机构
[1] ASTAR, Singapore Immunol Network, Singapore 138648, Singapore
[2] Hosp La Paz, Tumor Immunol Lab, IdiPaz, Madrid 28046, Spain
[3] Natl Univ Hlth Syst, Dept Surg, Singapore 119228, Singapore
关键词
NF-KAPPA-B; BLOOD MONOCYTES; ENDOTOXIN TOLERANCE; GENE-EXPRESSION; MACROPHAGE ACTIVATION; PROFILING REVEALS; PERIPHERAL-BLOOD; ALPHA PRODUCTION; DENDRITIC CELLS; RECEPTOR;
D O I
10.4049/jimmunol.1100244
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Blood monocytes recognize Gram-negative bacteria through the TLR4, which signal via MyD88- and TRIF-dependent pathway to trigger an immune-inflammatory response. However, a dysregulated inflammatory response by these cells often leads to severe pathologies such as sepsis. We investigated the role of CD16 in the regulation of human monocyte response to Gram-negative endotoxin and sepsis. Blood monocytes from sepsis patients demonstrated an upregulation of several TRIF-dependent genes as well as a selective expansion of CD16-expressing (CD16(+)) monocytes. Gene expression and biochemical studies revealed CD16 to regulate the TRIF-dependent TLR4 pathway in monocytes by activating Syk, IFN regulatory factor 3, and STAT1, which resulted in enhanced expression of IFNB, CCL5, and CXCL10. CD16 also upregulated the expression of IL-1R-associated kinase M and IL-1 receptor antagonist, which are negative regulators of the MyD88-dependent pathway. CD16 overexpression or small interfering RNA knockdown in monocytes confirmed the above findings. Interestingly, these results were mirrored in the CD16(+) monocyte subset isolated from sepsis patients, providing an in vivo confirmation to our findings. Collectively, the results from the current study demonstrate CD16 as a key regulator of the TRIF-dependent TLR4 pathway in human monocytes and their CD16-expressing subset, with implications in sepsis. The Journal of Immunology, 2012, 188: 3584-3593.
引用
收藏
页码:3584 / 3593
页数:10
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