Inactivation Of Interleukin-4 Receptor Alpha 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 alpha (IL-4R alpha) signaling is importantly involved in cardiovascular remodeling, however, the target cell type(s) is unclear. Here, we investigated the role of myeloid-specific IL-4R alpha signaling in cardiovascular remodeling induced by angiotensin II and high salt.METHODS AND RESULTS: Myeloid IL-4R alpha 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 Relm alpha/Fizz1 (resistin-like molecule alpha). After angiotensin II and high salt treatment, myeloid-specific IL-4R alpha deficiency did not change hypertrophic remodeling within the heart and aorta. However, myeloid IL-4R alpha 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 MyIL4R alpha KO mice and was mediated by attenuated alternative macrophage activation.CONCLUSIONS: Myeloid IL-4R alpha signaling is substantially involved in fibrotic cardiovascular remodeling by controlling alternative macrophage activation and regulating fibrosis-related signaling. Inhibiting myeloid IL-4R alpha signaling may be a potential strategy to prevent hypertensive cardiovascular diseases.