IL‐25 Supplementation Induces M2 Macrophage Polarization, Reduces Blood Pressure, and Improves Fetal Weight in Placental Ischemic Rats

Abstract

Preeclampsia (PE) is characterized by maternal hypertension, intrauterine growth restriction (IUGR), and increased macrophage activation. Macrophages can be broadly categorized into pro‐inflammatory M1 macrophages (M1s) and anti‐inflammatory M2 macrophages (M2s). The M1:M2 ratio is significantly increased in PE women. However, the precise contribution of increased M1s to PE pathophysiology remains unclear. Using the reduced uterine perfusion pressure (RUPP) rat model of placental ischemia, we tested the hypothesis that supplementation of RUPP rats with IL‐25, a cytokine that drives macrophage polarization to anti‐inflammatory M2s, will increase M2s, decrease mean arterial pressure (MAP), and improve fetal growth. On gestation day (GD) 14, timed pregnant 10‐12 week old Sprague Dawley rats underwent the RUPP or Sham procedure and a mini‐osmotic pump infusing IL‐25 (0.5µg/day) or vehicle was implanted i.p., in both groups. Carotid catheters were placed on GD18. On GD19, MAP was measured, animals were euthanized, and blood and tissues were collected for analysis. Flow cytometry analysis was performed on placental and renal tissues. M2 macrophages (CD3‐/CD68+/CD163+) were markedly reduced in placentas of RUPP rats compared to Sham (0.2% vs. 4.2% of total macrophages) and in kidneys of RUPP rats vs. Sham (0.19% vs. 1.445% total of macrophages). IL‐25 supplementation elevated M2 populations in placental (3.985%) and renal (5.985%) tissues of RUPP. Likewise, IL‐25 treatment increased M2 macrophages in Sham placental (18.56%) and renal (12.99%) tissues. Increased MAP was observed in RUPP rats compared with Sham (123.5 mmHg vs. 106.5 mmHg, respectively) and was reduced in RUPP + IL‐25 (107.5 mmHg). No changes were observed in MAP of Sham rats treated with IL‐25. Fetal weights were reduced in RUPP vs. Sham (2.035g vs. 2.405g, respectively) and were normalized in RUPP after IL‐25 supplementation (2.425g). IL‐25 supplementation had no effect on fetal weight of Sham rats. Additional analyses will include assessment of blood and tissue cytokines and reactive oxygen species, and vascular function in all groups. In conclusion, IL‐25 supplementation increased placental and renal anti‐inflammatory M2 macrophage populations, reduced MAP, and improved fetal weights in RUPP recipients. These data suggest that macrophage activation is a key contributor to PE pathophysiology and may represent a therapeutic target to improve maternal and fetal outcomes in PE.