title: Interleukin receptor activates a MYD88-ARNO-ARF6 cascade to disrupt vascular stability.
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.
authors.affiliation: Department of Medicine, University of Utah, Salt Lake City, Utah 84112, USA.
authors.forename: Weiquan
authors.initials: W
authors.lastname: Zhu
authors.forename: Nyall R
authors.initials: NR
authors.lastname: London
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Gibson
authors.forename: Chadwick T
authors.initials: CT
authors.lastname: Davis
authors.forename: Zongzhong
authors.initials: Z
authors.lastname: Tong
authors.forename: Lise K
authors.initials: LK
authors.lastname: Sorensen
authors.forename: Dallas S
authors.initials: DS
authors.lastname: Shi
authors.forename: Jinping
authors.initials: J
authors.lastname: Guo
authors.forename: Matthew C P
authors.initials: MC
authors.lastname: Smith
authors.forename: Allie H
authors.initials: AH
authors.lastname: Grossmann
authors.forename: Kirk R
authors.initials: KR
authors.lastname: Thomas
authors.forename: Dean Y
authors.initials: DY
authors.lastname: Li
mesh_terms: D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000378:metabolism*; D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D001168:Arthritis / Q000473:pathology; D015820:Cadherins / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects; D002460:Cell Line; D042783:Endothelial Cells / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D011687:Purines / Q000494:pharmacology; D018123:Receptors, Interleukin / Q000378:metabolism*; D015398:Signal Transduction; D013876:Thiophenes / Q000494:pharmacology
chemical_list: D000089982:ADP-Ribosylation Factor 6; D000276:Adjuvants, Immunologic; D015820:Cadherins; D020690:GTPase-Activating Proteins; D053583:Interleukin-1beta; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D011687:Purines; C520339:QS11 compound; D018123:Receptors, Interleukin; C477523:SC 514; D013876:Thiophenes; C102474:cytohesin-2; D020727:ADP-Ribosylation Factors; C000715348:ARF6 protein, human