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 recruitment1–4. 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 response5,6. Paradoxically, the same cytokines vital to a successful immune defense also have disruptive effects on endothelial cell-cell interactions and can trigger degradation of barrier function and dissociation of tissue architecture7–9. The mechanism of this barrier dissolution and its relationship to the canonical NF-κB pathway remains ill defined. Here we show that the direct, immediate, and disruptive effects of IL-1β on endothelial stability are NF-κB independent and are instead the result of signaling via the small GTPase, ADP-ribosylation factor 6 (ARF6), and its activator, ARF nucleotide binding site opener (ARNO). Moreover, we show that ARNO binds directly to the adaptor protein MYD88, and thus propose MYD88-ARNO-ARF6 as a proximal IL-1β signaling pathway distinct from that mediated by NF-κB (Supplementary Fig. 1). Finally, we show that SecinH3, an inhibitor of ARF guanine nucleotide-exchange factors (GEFs) such as ARNO, enhances vascular stability and significantly improves outcomes in animal models of inflammatory arthritis and acute inflammation.

Neutrophils Mediate Blood–Spinal Cord Barrier Disruption in Demyelinating Neuroinflammatory Diseases

“…In the periphery, cytokines and chemokines released by circulating effector cells such as T cells and neutrophils are also known to affect CNS barrier homeostasis. Notably, IL-1b has been shown to modulate BBB permeability in mice and rats and to activate human ECs (7,81,82). Interestingly, we found in the present study that blocking or deleting the endothelial IL-1R1 prevents the adhesion of circulating neutrophils to the spinal cord endothelium and delays EAE onset.…”

“…In the animal model of MS, experimental autoimmune encephalomyelitis (EAE), the BSCB is compromised, thereby exposing the fragile CNS environment to the immune system and its cellular arsenal. This leads to immune cell invasion, formation of demyelinated lesions, and axonal damage (4,(6)(7)(8). Early breakdown of the BSCB in EAE has been widely documented, but the precise timing and triggers of this disruption are still a matter of debate (9)(10)(11)(12).…”

The Small GTPase Arf6 Is Essential for the Tram/Trif Pathway in TLR4 Signaling

“…ARNO-Arf6 pathway to affect vascular endothelium cell-cell interactions, but Arf6 is not required for the IL-1␤-induced NF-B activation (26). We find that TLR2-dependent NF-B activation is also independent of Arf6.…”

“…Arf6 is required for TLR9 signaling via the regulation of cellular uptake of CpG oligodeoxynucleotides (ODN) (25). Arf6 also mediates interleukin-1␤ (IL-1␤) induced vascular endothelium stability (26). Both TLR9 and the IL-1␤ receptor use MyD88, but not Mal for their signal transduction (25)(26)(27).…”

Arf6 regulates tumour angiogenesis and growth through HGF-induced endothelial β1 integrin recycling

“…More recently, it has been demonstrated that interleukin 1b regulates endothelial cell permeability through Arf6 activation to allow inflammatory cells to be recruited to inflammatory sites 43 . Taken together, these reports suggest that VEGF-stimulated Arf6 pathways and functions might be revealed through the study of different model systems.…”