Inactivation of Interleukin-4 Receptor α Signaling in Myeloid Cells Protects Mice From Angiotensin II/High Salt-Induced Cardiovascular Dysfunction Through Suppression of Fibrotic Remodeling.

Background Hypertension-induced cardiovascular remodeling is characterized by chronic low-grade inflammation. Interleukin-4 receptor α (IL-4Rα) signaling is importantly involved in cardiovascular remodeling, however, the target cell type(s) is unclear. Here, we investigated the role of myeloid-specific IL-4Rα signaling in cardiovascular remodeling induced by angiotensin II and high salt. Methods and Results Myeloid IL-4Rα deficiency suppressed both the in vitro and in vivo expression of alternatively activated macrophage markers including Arg1 (arginase 1), Ym1 (chitinase 3-like 3), and Relmα/Fizz1 (resistin-like molecule α). After angiotensin II and high salt treatment, myeloid-specific IL-4Rα deficiency did not change hypertrophic remodeling within the heart and aorta. However, myeloid IL-4Rα deficiency resulted in a substantial reduction in fibrosis through the suppression of profibrotic pathways and the enhancement of antifibrotic signaling. Decreased fibrosis was associated with significant preservation of myocardial function in MyIL4RαKO mice and was mediated by attenuated alternative macrophage activation. Conclusions Myeloid IL-4Rα signaling is substantially involved in fibrotic cardiovascular remodeling by controlling alternative macrophage activation and regulating fibrosis-related signaling. Inhibiting myeloid IL-4Rα signaling may be a potential strategy to prevent hypertensive cardiovascular diseases.