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

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.

• Authors: Fengge Zhu, Xueyuan Bai, Quan Hong, Shaoyuan Cui, Xu Wang, Fengjun Xiao, Jin Li, Li Zhang, Zheyi Dong, Yong Wang, Guangyan Cai, Xiangmei Chen
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 203 Issue 10 Pg. 2644-2654 (11 15 2019) ISSN: 1550-6606 [Electronic] United States
• PMID: 31591147 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 by The American Association of Immunologists, Inc.

Chemical References

• Aminosalicylic Acids
• BP-1-102
• Il33 protein, mouse
• Interleukin-33
• STAT3 Transcription Factor
• Stat3 protein, mouse
• Sulfonamides

Topics

• Adaptation, Physiological (drug effects)
• Aminosalicylic Acids (pharmacology)
• Animals
• Bone Marrow (metabolism)
• Cells, Cultured
• Disease Models, Animal
• Fibroblasts (metabolism)
• Fibrosis
• Interleukin-33 (metabolism, pharmacology)
• Kidney (pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Monocytes (metabolism)
• STAT3 Transcription Factor (antagonists & inhibitors)
• Sulfonamides (pharmacology)
• Ureteral Obstruction (metabolism)