Interleukin receptor activates a MYD88-ARNO-ARF6 cascade to disrupt vascular stability

Weiquan Zhu, Nyall R. London, Christopher C. Gibson, Chadwick T. Davis, Zongzhong Tong, Lise K. Sorensen, Dallas S. Shi, Jinping Guo, Matthew C.P. Smith, Allie H. Grossmann, Kirk R. Thomas, Dean Y. Li

Research output: Contribution to journalArticle

Abstract

The innate immune response is essential for combating infectious disease. Macrophages and other cells respond to infection by releasing cytokines, such as interleukin-1β (IL-1β), which in turn activate a well-described, myeloid-differentiation factor 88 (MYD88)-mediated, nuclear factor-κB (NF-κB)-dependent transcriptional pathway that results in inflammatory-cell activation and recruitment. Endothelial cells, which usually serve as a barrier to the movement of inflammatory cells out of the blood and into tissue, are also critical mediators of the inflammatory response. Paradoxically, the cytokines vital to a successful immune defence also have disruptive effects on endothelial cell-cell interactions and can trigger degradation of barrier function and dissociation of tissue architecture. The mechanism of this barrier dissolution and its relationship to the canonical NF-κB pathway remain poorly defined. Here we show that the direct, immediate and disruptive effects of IL-1β on endothelial stability in a human in vitro cell model are NF-κB independent and are instead the result of signalling through the small GTPase ADP-ribosylation factor 6 (ARF6) and its activator ARF nucleotide binding site opener (ARNO; also known as CYTH2). Moreover, we show that ARNO binds directly to the adaptor protein MYD88, and thus propose MYD88-ARNO-ARF6 as a proximal IL-1β signalling pathway distinct from that mediated by NF-κB. Finally, we show that SecinH3, an inhibitor of ARF guanine nucleotide-exchange factors such as ARNO, enhances vascular stability and significantly improves outcomes in animal models of inflammatory arthritis and acute inflammation.

Original languageEnglish (US)
Pages (from-to)252-255
Number of pages4
JournalNature
Volume492
Issue number7428
DOIs
StatePublished - Dec 13 2012
Externally publishedYes

ASJC Scopus subject areas

  • General

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    Zhu, W., London, N. R., Gibson, C. C., Davis, C. T., Tong, Z., Sorensen, L. K., Shi, D. S., Guo, J., Smith, M. C. P., Grossmann, A. H., Thomas, K. R., & Li, D. Y. (2012). Interleukin receptor activates a MYD88-ARNO-ARF6 cascade to disrupt vascular stability. Nature, 492(7428), 252-255. https://doi.org/10.1038/nature11603