title: Chronic Inhibition of PDE5 Limits Pro-Inflammatory Monocyte-Macrophage Polarization in Streptozotocin-Induced Diabetic Mice.
abstract: Diabetes mellitus is characterized by changes in endothelial cells that alter monocyte recruitment, increase classic (M1-type) tissue macrophage infiltration and lead to self-sustained inflammation. Our and other groups recently showed that chronic inhibition of phosphodiesterase-5 (PDE5i) affects circulating cytokine levels in patients with diabetes; whether PDE5i also affects circulating monocytes and tissue inflammatory cell infiltration remains to be established. Using murine streptozotocin (STZ)-induced diabetes and in human vitro cell-cell adhesion models we show that chronic hyperglycemia induces changes in myeloid and endothelial cells that alter monocyte recruitment and lead to self-sustained inflammation. Continuous PDE5i with sildenafil (SILD) expanded tissue anti-inflammatory TIE2-expressing monocytes (TEMs), which are known to limit inflammation and promote tissue repair. Specifically, SILD: 1) normalizes the frequency of circulating pro-inflammatory monocytes triggered by hyperglycemia (53.7 ± 7.9% of CD11b+Gr-1+ cells in STZ vs. 30.4 ± 8.3% in STZ+SILD and 27.1 ± 1.6% in CTRL, P<0.01); 2) prevents STZ-induced tissue inflammatory infiltration (4-fold increase in F4/80+ macrophages in diabetic vs. control mice) by increasing renal and heart anti-inflammatory TEMs (30.9 ± 3.6% in STZ+SILD vs. 6.9 ± 2.7% in STZ, P <0.01, and 11.6 ± 2.9% in CTRL mice); 3) reduces vascular inflammatory proteins (iNOS, COX2, VCAM-1) promoting tissue protection; 4) lowers monocyte adhesion to human endothelial cells in vitro through the TIE2 receptor. All these changes occurred independently from changes of glycemic status. In summary, we demonstrate that circulating renal and cardiac TEMs are defective in chronic hyperglycemia and that SILD normalizes their levels by facilitating the shift from classic (M1-like) to alternative (M2-like)/TEM macrophage polarization. Restoration of tissue TEMs with PDE5i could represent an additional pharmacological tool to prevent end-organ diabetic complications.
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Mary Anna
authors.initials: MA
authors.lastname: Venneri
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Giannetta
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Panio
authors.affiliation: Department of Anatomical, Histological, Forensic and Orthopedic Sciences, Sapienza University, Rome, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: De Gaetano
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Gianfrilli
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Pofi
authors.affiliation: Department of Anatomical, Histological, Forensic and Orthopedic Sciences, Sapienza University, Rome, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Masciarelli
authors.affiliation: Department of Anatomical, Histological, Forensic and Orthopedic Sciences, Sapienza University, Rome, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Fazi
authors.affiliation: Department of Medicine and Health Sciences, University of Molise, Campobasso, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Pellegrini
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Lenzi
authors.affiliation: Department of Anatomical, Histological, Forensic and Orthopedic Sciences, Sapienza University, Rome, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Naro
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Isidori
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002450:Cell Communication / Q000187:drug effects; D002452:Cell Count; D018920:Coculture Techniques; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000235:genetics* / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D005786:Gene Expression Regulation; D006943:Hyperglycemia / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology*; D020011:Protective Agents / Q000494:pharmacology*; D042787:Receptor, TIE-2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000068677:Sildenafil Citrate / Q000494:pharmacology*; D013311:Streptozocin; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D058986:Phosphodiesterase 5 Inhibitors; D020011:Protective Agents; D019010:Vascular Cell Adhesion Molecule-1; D013311:Streptozocin; D000068677:Sildenafil Citrate; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D042787:Receptor, TIE-2; C079086:Tek protein, mouse; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517382:Pde5a protein, mouse