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.
SUMMARY
Activating mutations in Gαq proteins, which form the a subunit of certain heterotrimeric G proteins, drive uveal melanoma oncogenesis by triggering multiple downstream signaling pathways, including PLC/PKC, Rho/Rac, and YAP. Here we show that the small GTPase ARF6 acts as a proximal node of oncogenic Gαq signaling to induce all of these downstream pathways as well as β-catenin signaling. ARF6 activates these diverse pathways through a common mechanism—the trafficking of GNAQ and β-catenin from the plasma membrane to cytoplasmic vesicles and the nucleus, respectively. Blocking ARF6 with a small molecule reduces uveal melanoma cell proliferation and tumorigenesis in a mouse model, confirming the functional relevance of this pathway and suggesting a therapeutic strategy for Gα-mediated diseases.
Intracameral cefuroxime and moxifloxacin reduced endophthalmitis rates compared with controls with minimal or no toxicity events at standard doses. Additionally, intracameral antibiotics alone may be as effective as intracameral plus topical antibiotics.
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