STAT3 Inhibition Partly Abolishes IL-33–Induced Bone Marrow–Derived Monocyte Phenotypic Transition into Fibroblast Precursor and Alleviates Experimental Renal Interstitial Fibrosis

Abstract

Abstract Previous studies of Jak–STAT inhibitors have shown promise in treating kidney diseases. The activation of Jak–STAT components is important in cell fate determination in many cell types, including bone marrow–derived cells, which are important contributors in renal interstitial fibrosis. In this study, we tested the effect of a new STAT3 inhibitor, BP-1-102, on monocyte-to-fibrocyte transition and the progression of renal interstitial fibrosis. We tested the effect of BP-1-102 in a mouse model of unilateral ureteral obstruction in vivo and IL-33-treated bone marrow–derived monocytes in vitro. BP-1-102 treatment alleviated renal interstitial fibrosis, reduced collagen deposition and extracellular matrix protein production, inhibited inflammatory cell infiltration, suppressed the percentage of CD45+ PDGFRβ+, CD45+ CD34− Col I+ and CD45+ CD11b+ Col I+ cells within the obstructed kidney and reduced the mRNA levels of the proinflammatory and profibrotic cytokines IL-1β, TGF-β, TNF-α, ICAM-1, and CXCL16. In vitro, BP-1-102 inhibited the IL-33–induced phenotypic transition into fibroblast precursors in bone marrow–derived monocytes, marked by reduced CD45+ CD34− Col I+ and CD45+ CD11b+ Col I+ cell percentage. Our results indicate a potential mechanism by which the STAT3 inhibitor BP-1-102 inhibits bone marrow–derived monocyte transition into fibroblast precursors in an IL-33/STAT3–dependent manner and thereby alleviates renal interstitial fibrosis.