Editors' ChoiceImmunology

New connections: Species-specific immune responses

Sci. Signal.  19 Apr 2016:
Vol. 9, Issue 424, pp. ec92
DOI: 10.1126/scisignal.aaf8944

In mouse macrophages, production of the proinflammatory cytokine interleukin-1β (IL-1β) is a two-step process. First, activation of the transcription factor nuclear factor κB (NF-κB), such as by the Toll-like receptor 4 (TLR4) agonist lipopolysaccharide (LPS), leads to the production of pro–IL-1β. Second, detection of a microbial or host danger signal results in the formation of the NLRP3 inflammasome, a multiprotein complex (pyroptosome) containing caspase 1, which cleaves pro–IL-1β to generate the mature form of the cytokine. However, human monocytes produce IL-1β in response to LPS without the need for a danger signal. Gaidt et al. found that this was because of the LPS-induced stimulation of an alternative pathway that depended on the TLR4 adaptor TRIF and caspase-8 upstream of NLRP3, but which did not lead to pyroptosome assembly. This human-specific response differed from classical inflammasome activation by being independent of K+ efflux, which triggers NLRP3 activation, and by not inducing pyroptosis, a form of cell death. These findings reflect a study in Science Signaling by Sun et al. that used an RNA interference (RNAi)–based screen to compare the responses of mouse and human macrophages to different TLR agonists. Although both cell types used many of the same signaling molecules, they exhibited species-specific differences in their use of members of the IRAK family of kinases downstream of TLRs, with human macrophages depending on IRAK1, whereas mouse macrophages relied on IRAK2 and IRAK4. Together, these studies highlight important species-specific differences in the use of signaling components to respond to common threats, which may be useful in designing therapies to modulate human TLR-dependent immune responses.

M. M. Gaidt, T. S. Ebert, D. Chauhan, T. Schmidt, J. L. Schmid-Burgk, F. Rapino, A. A. B. Robertson, M. A. Cooper, T. Graf, V. Hornung, Human monocytes engage an alternative inflammasome pathway. Immunity 10.1016/j.immuni.2016.01.012 (2016). [PubMed]

J. Sun, N. Li, K.-S. Oh, B. Dutta, S. J. Vayttaden, B. Lin, T. S. Ebert, D. De Nardo, J. Davis, R. Bagirzadeh, N. W. Lounsbury, C. Pasare, E. Latz, V. Hornung, I. D. C. Fraser, Comprehensive RNAi-based screening of human and mouse TLR pathways identifies species-specific preferences in signaling protein use. Sci. Signal. 9, ra3 (2016). [Abstract]

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