期刊
SCIENCE SIGNALING
卷 9, 期 409, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.aab2191
关键词
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资金
- National Institute of Allergy and Infectious Diseases (NIAID)
- BONFOR research commission at the University of Bonn
- German Research Foundation [SFB704, SFB670]
- European Research Council [ERC-2009-StG 243046]
- NIH [R01HL112661]
- Deutsche Forschungsgemeinschaft [SFB670]
- European Research Council (ERC InflammAct)
- NIAID [AI082265]
- Welch Foundation [I-1820]
- NIH Integrative Immunology Training program grant [5T32-AI005284-35]
Toll-like receptors (TLRs) are a major class of pattern recognition receptors, whichmediate the responses of innate immune cells to microbial stimuli. To systematically determine the roles of proteins in canonical TLR signaling pathways, we conducted an RNA interference (RNAi)-based screen in human and mouse macrophages. We observed a pattern of conserved signaling module dependencies across species, but found notable species-specific requirements at the level of individual proteins. Among these, weidentified unexpected differences in the involvement of members of the interleukin-1 receptor-associated kinase (IRAK) family between the human andmouse TLR pathways. Whereas TLR signaling inmousemacrophages depended primarily on IRAK4 and IRAK2, with little or no role for IRAK1, TLR signaling and proinflammatory cytokine production in human macrophages depended on IRAK1, with knockdown of IRAK4 or IRAK2 having less of an effect. Consistent with species-specific roles for these kinases, IRAK4 orthologs failed to rescue signaling in IRAK4-deficient macrophages from the other species, and only mouse macrophages required the kinase activity of IRAK4 to mediate TLR responses. The identification of a critical role for IRAK1 in TLR signaling in humans could potentially explain the association of IRAK1 with several autoimmune diseases. Furthermore, this study demonstrated how systematic screening can be used to identify important characteristics of innate immune responses across species, which could optimize therapeutic targeting to manipulate human TLR-dependent outputs.
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