Inflammatory and autoimmune diseases have a major impact on health care in the United States. For example, rheumatoid arthritis (RA) affects approximately 1.3 million American adults. In its progressive form the disease has debilitating effects including painful inflammation and destruction of the joints of the fingers, wrists, knees, hips, and vertebral column and leads to reduced life expectancy. Vascular instability and angiogenesis are hallmarks of RA and other inflammatory diseases. Indeed, a breakdown of the vascular endothelium may be the critical first step in the pathogenesis of many autoimmue diseases including RA. Arthritis-inducing cytokines, such as TNF-? and IL-1, signal through a pathway that activates NF-?B and increases the transcription of target genes that fight infection. Many RA patients are treated with biologic agents that inhibit this pathway but by doing so, leave the patient immunocompromised. We have recently identified a molecular pathway that is activated by IL-1 but diverges from the canonical NF-?B-pathway at the level of the IL-1R adapter protein MYD88. MYD88 binds to ARNO, an ARF-GEF that activates the small GTPase ARF6. Active ARF6 disrupts adherens junctions by reducing the levels of cell surface VE-cadherin, which leads to vascular destabilization and increased permeability. We have shown that blocking the activity of ARF6 by inhibiting its activation with the ARF6 small molecule inhibitor SecinH3 reduces both the progression of arthritis and acute inflammation in standard in vivo mouse models of human disease without inhibiting NF-?B activation and rendering the mouse immunocompromised. We hypothesize that the activation of ARF6 is common to all RA-inducing inflammatory pathways and that inhibiting ARF6 activation would reduce vascular permeability and its debilitating sequelae without affecting the beneficial immunomodulatory effects arising from NF-?B activation. If true, we would expect that mice harboring endothelial-specific deficiencies in Arf6 or other members of this divergent pathway would exhibit marked resiliency in mouse models of arthritis and acute inflammation but would not be immunosuppressed. We will test our hypothesis by pursuing the following three aims.
In Aim 1, we will examine the roles of ARF6 and NF-?B in controlling endothelial barrier function following TNF-? receptor (TNFR) and toll-like receptor (TLR) stimulation.
In Aim 2, we will examine whether TNFR- and TLR-dependent inflammatory pathways induce endothelial permeability by activating ARF-GEFs and disrupting adherens junctions.
In Aim 3, we will determine whether endothelial expression of ARF6 is required for arthritic progression and acute inflammation in mouse models of these diseases. The successful completion of these aims will allow us to assess whether this divergent pathway controls cytokine-induced vascular permeability and arthritic progression in mouse disease models and would indicate whether the pursuit of therapeutic strategies to inhibit this pathway might be a useful approach for treating rheumatoid arthritis and other related inflammatory diseases.
Current therapies for the treatment of inflammatory diseases such as rheumatoid arthritis often leave the patient more susceptible to infection. We have recently identified a novel molecular pathway that may be responsible for arthritic progression in animal models of disease but does not appear to affect the immune response. We will determine whether this pathway indeed controls the initiation and progression of arthritis and if so, drugs developed in the future that target this pathway may reduce the progression of inflammatory diseases without making the patient more susceptible to infection.
| Zhu, Weiquan; Shi, Dallas S; Winter, Jacob M et al. (2017) Small GTPase ARF6 controls VEGFR2 trafficking and signaling in diabetic retinopathy. J Clin Invest 127:4569-4582 |
| Yoo, Jae Hyuk; Shi, Dallas S; Grossmann, Allie H et al. (2016) ARF6 Is an Actionable Node that Orchestrates Oncogenic GNAQ Signaling in Uveal Melanoma. Cancer Cell 29:889-904 |
| Grossmann, Allie H; Zhao, Helong; Jenkins, Noah et al. (2016) The small GTPase ARF6 regulates protein trafficking to control cellular function during development and in disease. Small GTPases :1-12 |
| Gibson, Christopher C; Davis, Chadwick T; Zhu, Weiquan et al. (2015) Dietary Vitamin D and Its Metabolites Non-Genomically Stabilize the Endothelium. PLoS One 10:e0140370 |
| Gibson, Christopher C; Zhu, Weiquan; Davis, Chadwick T et al. (2015) Strategy for identifying repurposed drugs for the treatment of cerebral cavernous malformation. Circulation 131:289-99 |
| Davis, Chadwick T; Zhu, Weiquan; Gibson, Christopher C et al. (2014) ARF6 inhibition stabilizes the vasculature and enhances survival during endotoxic shock. J Immunol 192:6045-52 |
| Shi, Dallas S; Smith, Matthew C P; Campbell, Robert A et al. (2014) Proteasome function is required for platelet production. J Clin Invest 124:3757-66 |
