The Role of PDE8 in T Cell Recruitment and Function in Inflammation.

Paul M Epstein,Chaitali Basole,Stefan Brocke

doi:10.3389/fcell.2021.636778

Paul M Epstein, Chaitali Basole + Show 1 more

Open Access

https://doi.org/10.3389/fcell.2021.636778

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Abstract

Inhibitors targeting cyclic nucleotide phosphodiesterases (PDEs) expressed in leukocytes have entered clinical practice to treat inflammatory disorders, with three PDE4 inhibitors currently in clinical use as therapeutics for psoriasis, psoriatic arthritis, atopic dermatitis and chronic obstructive pulmonary disease. In contrast, the PDE8 family that is upregulated in pro-inflammatory T cells is a largely unexplored therapeutic target. It was shown that PDE8A plays a major role in controlling T cell and breast cancer cell motility, including adhesion to endothelial cells under physiological shear stress and chemotaxis. This is a unique function of PDE8 not shared by PDE4, another cAMP specific PDE, employed, as noted, as an anti-inflammatory therapeutic. Additionally, a regulatory role was shown for the PDE8A-rapidly accelerated fibrosarcoma (Raf)-1 kinase signaling complex in myelin antigen reactive CD4+ effector T cell adhesion and locomotion by a mechanism differing from that of PDE4. The PDE8A-Raf-1 kinase signaling complex affects T cell motility, at least in part, via regulating the LFA-1 integrin mediated adhesion to ICAM-1. The findings that PDE8A and its isoforms are expressed at higher levels in naive and myelin oligodendrocyte glycoprotein (MOG)35–55 activated effector T (Teff) cells compared to regulatory T (Treg) cells and that PDE8 inhibition specifically affects MOG35–55 activated Teff cell adhesion, indicates that PDE8A could represent a new beneficial target expressed in pathogenic Teff cells in CNS inflammation. The implications of this work for targeting PDE8 in inflammation will be discussed in this review.

Highlights

With over 800 members identified in humans, G protein coupled receptors (GPCRs) constitute a large group of signaling molecules expressed on many cells
The PDE8ARaf-1 kinase signaling complex has been identified as a functional site for PDE8A controlling T cell motility (Figure 1)
Inasmuch as treatment with the peptide designed to disrupt the PDE8A-Raf1 complex led to phosphorylation of rapidly accelerated fibrosarcoma (Raf)-1 at an inhibitory site but phosphorylation of ERK1/2 at activating sites, it suggests that PDE8 displacement from the complex exerts a Raf-1 dependent but EXTRACELLULAR SIGNAL-REGULATED KINASE (ERK) independent effect on T cell motility

Summary

Introduction

With over 800 members identified in humans, G protein coupled receptors (GPCRs) constitute a large group of signaling molecules expressed on many cells. It was shown that PDE8A regulates motility of lymphocytes and breast cancer cells, including adhesion to endothelial cells under physiological shear stress and chemotaxis (Dong et al, 2006, 2015; Vang et al, 2010, 2013; Basole et al, 2017). PDE8 inhibition study ex vivo and in vitro PDE8A1/PDE8A2 Expression study PDE8A and B/ Regulating T cell adhesion through inhibitor and peptide disruptor study PDE 4–8, 10, and 11/Use of broad PDE inhibitor dipyridamole in vivo treatment PDE8A-C-Raf complex/PDE8A-C-Raf complex disruptor PPL-008

Results

Conclusion