Research ArticleSystems Immunology

Comprehensive RNAi-based screening of human and mouse TLR pathways identifies species-specific preferences in signaling protein use

Sci. Signal.  05 Jan 2016:
Vol. 9, Issue 409, pp. ra3
DOI: 10.1126/scisignal.aab2191

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Species-specific TLR signaling

Whether mice are a good model for the study of innate immune responses in humans is a topic of some debate. Sun et al. used an RNA interference (RNAi)–based screen to compare the responses of mouse and human macrophage reporter cell lines to various ligands of Toll-like receptors (TLRs), which are pattern recognition receptors that stimulate innate immune responses. In addition to confirming the conservation of many TLR signaling components between the two species, the study revealed important differences in how mouse and human macrophages use members of the IRAK family of kinases, findings that have implications for the study and treatment of human autoimmune diseases.

Abstract

Toll-like receptors (TLRs) are a major class of pattern recognition receptors, which mediate 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, we identified unexpected differences in the involvement of members of the interleukin-1 receptor–associated kinase (IRAK) family between the human and mouse TLR pathways. Whereas TLR signaling in mouse macrophages 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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