The IL-4 receptor α has a critical role in bone marrow-derived fibroblast activation and renal fibrosis

Renal fibrosis is a common pathway leading to the progression of chronic kidney disease, and bone marrowderived fibroblasts contribute significantly to the development of renal fibrosis. However, the signaling mechanisms underlying the activation of these fibroblasts are not completely understood. Here, we examined the role of IL-4 receptor alpha (IL-4R alpha) in the activation of myeloid fibroblasts in two experimental models of renal fibrosis. Compared with wild-type mice, IL-4R alpha knockout mice accumulated fewer bone marrow-derived fibroblasts and myofibroblasts in their kidneys. IL-4R alpha deficiency suppressed the expression of alpha-smooth muscle actin, extracellular matrix proteins and the development of renal fibrosis. Furthermore, IL-4R alpha deficiency inhibited the activation of signal transducer and activator of transcription 6 (STAT6) in the kidney. Moreover, wild-type mice engrafted with bone marrow cells from IL-4R alpha knockout mice exhibited fewer myeloid fibroblasts in the kidney and displayed less severe renal fibrosis following ureteral obstructive injury compared with wild-type mice engrafted with wild-type bone marrow cells. In vitro, IL-4 activated STAT6 and stimulated expression of alpha-smooth muscle actin and fibronectin in mouse bone marrow monocytes. This was abolished in the absence of IL-4Ra. Thus, IL-4R alpha plays an important role in bone marrowderived fibroblast activation, resulting in extracellular matrix protein production and fibrosis development. Hence, the IL-4R alpha/STAT6 signaling pathway may serve as a novel therapeutic target for chronic kidney disease.