Targeting the PDE8A-Raf-1 kinase signaling complex to treat autoimmune inflammation

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Abstract The levels of cAMP are regulated by phosphodiesterases (PDE), which are targets for the treatment of inflammatory disorders. We previously showed that PDE8A regulates T cell motility. We report here that PDE8A exerts its control of T cell function through the Raf-1 kinase signaling pathway. To mimic T cell migration under physiologic conditions, we performed flow chamber assays. The highly PDE8-selective enzymatic inhibitor PF-04957325 significantly suppresses rolling and adhesion of in vivo MOG35-55 activated inflammatory CD4+ T effector (Teff) cells while interacting with inflamed brain endothelial cells under shear flow conditions. Recently, PDE8A was shown to associate with Raf-1 creating a compartment of low cAMP around Raf-1 thereby protecting it from protein kinase A mediated inhibitory phosphorylation. To test this in Teff cells, we used a cell permeable peptide (DP) that disrupts the PDE8A-Raf-1 signaling complex. Disruption of the PDE8A-Raf-1 complex by DP significantly reduces adhesion of Teff cells to endothelial cells. We further observed that disrupting PDE8A-Raf-1 through DP specifically reduces adhesion, spreading and locomotion of Teff cells while interacting with the vascular adhesion molecule ICAM-1. Our investigation of the effect of PDE8 inhibitor on chronic and relapsing-remitting experimental autoimmune encephalomyelitis (EAE) in vivo indicate suppression of clinical and histopathological signs of disease. Collectively, our studies demonstrate that PDE8A inhibition by enzymatic inhibitors or PDE8A-Raf-1 kinase signaling complex disruptors significantly decreases Teff cell adhesion and migration on endothelial cells, and represents a novel approach to treat autoimmune inflammation in vivo.

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