Abstract
After decades of development, inhibitors targeting cyclic nucleotide phosphodiesterases (PDEs) expressed in leukocytes have entered clinical practice for the treatment of inflammatory disorders, with three PDE4 inhibitors being in clinical use as therapeutics for psoriasis, psoriatic arthritis, chronic obstructive pulmonary disease and atopic dermatitis. In contrast, the PDE8 family that is upregulated in pro-inflammatory T cells is a largely unexplored therapeutic target. We have previously demonstrated a role for the PDE8A-Raf-1 kinase complex in the regulation of myelin oligodendrocyte glycoprotein peptide 35–55 (MOG35–55) activated CD4+ effector T cell adhesion and locomotion by a mechanism that differs from PDE4 activity. In this study, we explored the in vivo treatment of experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis (MS) induced in mice immunized with MOG using the PDE8-selective inhibitor PF-04957325. For treatment in vivo, mice with EAE were either subcutaneously (s.c.) injected three times daily (10 mg/kg/dose), or were implanted subcutaneously with Alzet mini-osmotic pumps to deliver the PDE8 inhibitor (15.5 mg/kg/day). The mice were scored daily for clinical signs of paresis and paralysis which were characteristic of EAE. We observed the suppression of the clinical signs of EAE and a reduction of inflammatory lesion formation in the CNS by histopathological analysis through the determination of the numbers of mononuclear cells isolated from the spinal cord of mice with EAE. The PDE8 inhibitor treatment reduces the accumulation of both encephalitogenic Th1 and Th17 T cells in the CNS. Our study demonstrates the efficacy of targeting PDE8 as a treatment of autoimmune inflammation in vivo by reducing the inflammatory lesion load.
Highlights
Introduction published maps and institutional affilWith more than 800 members characterized in humans, G protein-coupled receptors (GPCRs) constitute the largest class of membrane receptors
In order to examine whether the PDE8-mediated regulation of CD4+ T cell motility acts on inflammatory disease in vivo, we tested the effect of PF-04957325 in a T cell-mediated
Studies on the characterization of PDE in human lymphocytes led to the concept that they could serve as excellent targets for anti-inflammatory therapy, focusing on
Summary
With more than 800 members characterized in humans, G protein-coupled receptors (GPCRs) constitute the largest class of membrane receptors. Including their downstream signaling pathways, they are the targets for nearly 35% of all approved therapeutics [1]. Extracellular ligand binding to Gs-coupled GPCRs leads to cAMP synthesis via the activation of adenylyl cyclase and the conversion of ATP to cAMP. T cell activation leads to a temporary upregulation of cAMP, which is degraded by cyclic nucleotide phosphodiesterase (PDE) enzymes [3]. PDEs are the only enzymes which are known to hydrolyze cAMP and maintain spatial and temporal control over the cAMP gradients within a cell [4]. PDEs are divided into 11 different gene families based on their iations
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