Citation: Nguyen, H.O.; Tiberio, L.; Facchinetti, F.; Ripari, G.; Violi, V.; Villetti, G.; Salvi, V.; Bosisio, D. Modulation of Human Dendritic Cell Functions by Phosphodiesterase-4 Inhibitors: Potential Relevance for the Treatment of Respiratory Diseases. Pharmaceutics 2023, 15, 2254. https://doi.org/10.3390/ pharmaceutics15092254 Academic Editors: Gaia Codolo, Barbara Frossi and Teresa Zelante Received: 27 July 2023 Revised: 23 August 2023 Accepted: 29 August 2023 Published: 31 August 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). pharmaceutics Review Modulation of Human Dendritic Cell Functions by Phosphodiesterase-4 Inhibitors: Potential Relevance for the Treatment of Respiratory Diseases Hoang Oanh Nguyen 1 , Laura Tiberio 2 , Fabrizio Facchinetti 3 , Giulia Ripari 2 , Valentina Violi 2 , Gino Villetti 3 , Valentina Salvi 2, * and Daniela Bosisio 2, * 1 ImmunoConcEpT, CNRS UMR 5164, University of Bordeaux, 33000 Bordeaux, France; hnguyen@immuconcept.org 2 Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; laura.tiberio@unibs.it (L.T.); g.ripari@unibs.it (G.R.); v.violi@studenti.unibs.it (V.V.) 3 Department of Experimental Pharmacology and Translational Science, Corporate Pre-Clinical R&D, Chiesi Farmaceutici S.p.A., 43122 Parma, Italy; f.facchinetti@chiesi.com (F.F.); g.villetti@chiesi.com (G.V.) * Correspondence: valentina.salvi@unibs.it (V.S.); daniela.bosisio@unibs.it (D.B.) Abstract: Inhibitors of phosphodiesterase-4 (PDE4) are small-molecule drugs that, by increasing the intracellular levels of cAMP in immune cells, elicit a broad spectrum of anti-inflammatory effects. As such, PDE4 inhibitors are actively studied as therapeutic options in a variety of human diseases characterized by an underlying inflammatory pathogenesis. Dendritic cells (DCs) are checkpoints of the inflammatory and immune responses, being responsible for both activation and dampening depending on their activation status. This review shows evidence that PDE4 inhibitors modulate inflammatory DC activation by decreasing the secretion of inflammatory and Th1/Th17-polarizing cytokines, although preserving the expression of costimulatory molecules and the CD4+ T cell-activating potential. In addition, DCs activated in the presence of PDE4 inhibitors induce a preferential Th2 skewing of effector T cells, retain the secretion of Th2-attracting chemokines and increase the production of T cell regulatory mediators, such as IDO1, TSP-1, VEGF-A and Amphiregulin. Finally, PDE4 inhibitors selectively induce the expression of the surface molecule CD141/Thrombomodulin/BDCA-3. The result of such fine-tuning is immunomodulatory DCs that are distinct from those induced by classical anti-inflammatory drugs, such as corticosteroids. The possible implications for the treatment of respiratory disorders (such as COPD, asthma and COVID-19) by PDE4 inhibitors will be discussed. Keywords: cDC1; cDC2; pDC; monocyte-derived DC; tolerogenic DCs; CD80; CD86; IL-12; TNFα; Tanimilast 1. Introduction cAMP is a key modulator of inflammation whose intracellular levels are regulated through hydrolysis by various phosphodiesterases (PDEs) [1]. PDE4, in particular, is a fam- ily of four genes (PDE4A, PDE4B, PDE4C and PDE4D) encoding cAMP-specific enzymes sharing a highly conserved catalytic domain and prominently expressed in immune cells. PDE4 inhibitors increase cAMP intracellular levels by inhibiting cAMP hydrolysis, thus eliciting a broad spectrum of anti-inflammatory effects in virtually all cells of the immune system [2]. Because of this, the inhibition of PDE4 enzymes has been clinically investigated as a therapeutic strategy in a variety of pathological settings, including respira- tory, dermatological and immune diseases, as well as cognitive and affective disorders [3,4]. Dendritic cells (DCs) are a specialized population of antigen-presenting cells, serving as sentinels of innate immunity and key initiators of adaptive and anti-viral immune responses. Deregulated DC functions are one major pathogenetic determinant of virtually Pharmaceutics 2023, 15, 2254. https://doi.org/10.3390/pharmaceutics15092254 https://www.mdpi.com/journal/pharmaceutics