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Editorial on the Research Topic Cyclic nucleotide phosphodiesterases (PDEs) in immune regulation and inflammation Cyclic nucleotides are involved in many cellular functions and well-established regulator of immune responses and inflammation. Leukocytes play a critical role in inflammation and its modulation. Function and regulation of different subpopulations of T cells, B cells and NK cells, as well as myeloid cells, such as neutrophils, monocytes, macrophages, and dendritic cells involve activation of the cAMP pathway. Additionally, interactions between leukocytes and endothelial cells are critical during inflammatory lesion formation and can be regulated by cAMP/cGMP signaling. Cyclic nucleotides are degraded by cyclic nucleotide phosphodiesterase (PDE) enzymes. PDEs are the only enzymes known to hydrolyze cAMP/ cGMP and thereby maintain spatial and temporal control over pools of cAMP/cGMP within distinct cellular compartments. PDEs are divided into 11 different gene families based on their specificity for cAMP or cGMP, structural similarity and mode of regulation. While PDEs have been recognized early as potential drug targets for anti-inflammatory drugs, bringing specific PDE inhibitors into clinical use has faced decades of challenges, mostly due to dose-limiting side effects. Major progress has been made with the approval and clinical use of select PDE4 inhibitors to treat major human inflammatory diseases. PDE4-selective inhibitors are used for oral treatment of chronic obstructive pulmonary disease, psoriatic arthritis and plaque psoriasis as well as a topical treatment for atopic dermatitis. Recent advances demonstrate a role for inflammation involved in many neurodegenerative pathologies. Due to the unique roles of specific PDE isoforms to control distinct pools of cyclic nucleotides in leukocytes, additional PDEs became a focus to study potentially novel therapeutics for inflammatory disorders. First, basic molecular functions of PDEs cell regulation are addressed. Kurelic et al. show that PDE2A is upregulated during activation of effector/conventional CD4 + T cells in vitro Kurelic et al. Combining selective inhibitors studies, approaches to induce accumulation of cGMP through various activators and elegant real time FRET imaging, they demonstrate an increase of cAMP in non-activated and a decrease of cAMP in activated effector/conventional CD4 + T cells, presumably dependent on the expression of PDE2A. These studies could explain context dependent regulation of effector/conventional T cell activation and function and provide the basis for developing new therapeutic approaches to T cell mediated autoimmune disorders. Chinn et al. identify PDE4B as the primary PDE expressed in dendritic cells (DCs) and demonstrate using DC-specific depletion of Gαs that dynamic, bidirectional regulation of PDE4B expression acts as a key homeostatic regulator of cAMP levels in DCs Chinn et al. They further show that inhibition of PDE4B in Gαs-depleted DCs decreased Th2 cell differentiation, which in concert with the known phenotype of DC-selective Gαs depletion in mice suggests PDE4B inhibition as a target for Th2-allergic asthma. Golshiri et al. highlighted the complexities of exploring PDE function in disease settings, in this case the role of PDE1 in a mouse knockout model of smooth muscle cell (SMC) aging The editors of this Research Topic were funded by the NMSS, FWO, Fondation Charcot Stichting and the Smart Family Foundation. We express our gratitude to all the authors who have contributed to this Research Topic and to the reviewers for their valuable work.