Chronic Inhibition of PDE5 Limits Pro-Inflammatory Monocyte-Macrophage Polarization in Streptozotocin-Induced Diabetic Mice
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Mary Anna Venneri1, Elisa Giannetta1, Giuseppe Panio1
1Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
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.
Insights
Sildenafil (a PDE5 inhibitor) expands anti-inflammatory monocytes (TEMs) in diabetic mice, reducing inflammation and preventing tissue damage. This occurs independently of blood sugar levels, offering a potential treatment for diabetic complications.
Area of Science:
- Immunology and Inflammation
- Endocrinology and Metabolic Diseases
- Pharmacology
Background:
- Diabetes mellitus is characterized by endothelial cell changes, altered monocyte recruitment, and increased M1-type macrophage infiltration, leading to sustained inflammation.
- Previous research indicated phosphodiesterase-5 inhibitors (PDE5i) affect cytokine levels in diabetic patients, but their impact on monocytes and tissue inflammation was unclear.
Purpose of the Study:
- To investigate the effect of chronic PDE5 inhibition on circulating monocytes and tissue inflammatory cell infiltration in a murine model of diabetes.
- To determine if PDE5i, specifically sildenafil (SILD), can modulate pro-inflammatory monocytes and promote anti-inflammatory TIE2-expressing monocytes (TEMs) in diabetes.
Main Methods:
- Utilized a murine streptozotocin (STZ)-induced diabetes model and in vitro human endothelial cell adhesion assays.
- Administered continuous PDE5i (sildenafil) to diabetic mice and assessed changes in circulating monocyte populations, tissue macrophage infiltration, and vascular inflammatory markers.
- Quantified TIE2-expressing monocytes (TEMs) in circulation and tissues (kidney, heart), and measured inflammatory protein expression (iNOS, COX2, VCAM-1).
Main Results:
- Chronic hyperglycemia increased pro-inflammatory monocytes and tissue macrophage infiltration, which was normalized by sildenafil treatment.
- Sildenafil significantly expanded anti-inflammatory TEMs in the kidneys and heart of diabetic mice, reducing overall inflammatory cell infiltration.
- Sildenafil reduced vascular inflammatory proteins and decreased monocyte adhesion to endothelial cells in vitro, mediated via the TIE2 receptor, independent of glycemic control.
Conclusions:
- Circulating and tissue TEMs are impaired in chronic hyperglycemia, contributing to diabetes-related inflammation.
- Sildenafil effectively restores TEM levels and shifts macrophage polarization from M1-like to M2-like/TEM phenotypes in diabetic conditions.
- Restoring tissue TEMs with PDE5 inhibitors like sildenafil presents a promising therapeutic strategy to prevent end-organ damage in diabetes.
