STAT3 Inhibition Partly Abolishes IL-33-Induced Bone Marrow-Derived Monocyte Phenotypic Transition into Fibroblast
Fengge Zhu1, Xueyuan Bai1, Quan Hong1
1Department of Nephrology, Chinese People's Liberation Army General Hospital, Chinese People's Liberation Army Institute of Kidney Diseases, State Key Laboratory of Kidney Diseases, National Clinical Study Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases, Beijing 100853, People's Republic of China.
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.
Insights
A new STAT3 inhibitor, BP-1-102, effectively reduced renal interstitial fibrosis in mice by blocking the transition of bone marrow-derived monocytes into fibroblast precursors. This finding highlights a novel therapeutic strategy for kidney fibrosis.
Area of Science:
- Nephrology
- Immunology
- Cell Biology
Background:
- Janus kinase-Signal transducer and activator of transcription (Jak-STAT) pathway activation is crucial for cell fate, impacting kidney diseases.
- Bone marrow-derived cells are key contributors to renal interstitial fibrosis.
Purpose of the Study:
- To investigate the efficacy of a novel STAT3 inhibitor, BP-1-102, in mitigating renal interstitial fibrosis.
- To elucidate the mechanism by which BP-1-102 affects monocyte-to-fibroblast precursor transition.
Main Methods:
- Utilized a mouse model of unilateral ureteral obstruction (UUO) for in vivo studies.
- Examined the effects of BP-1-102 on IL-33-treated bone marrow-derived monocytes in vitro.
- Assessed fibrosis markers, inflammatory cell infiltration, and cytokine mRNA levels.
Main Results:
- BP-1-102 treatment significantly alleviated renal interstitial fibrosis, reducing collagen deposition and extracellular matrix production in the UUO mouse model.
- The inhibitor suppressed inflammatory cell infiltration and specific cell populations (CD45+ PDGFRβ+, CD45+ CD34- Col I+, CD45+ CD11b+ Col I+) in fibrotic kidneys.
- In vitro, BP-1-102 inhibited IL-33-induced monocyte transition into fibroblast precursors, indicated by reduced CD45+ CD34- Col I+ and CD45+ CD11b+ Col I+ cell percentages.
Conclusions:
- The STAT3 inhibitor BP-1-102 demonstrates potential in treating renal interstitial fibrosis.
- BP-1-102 acts by inhibiting the IL-33/STAT3-dependent transition of bone marrow-derived monocytes into fibroblast precursors.
- This study provides a mechanistic basis for using STAT3 inhibitors as a therapeutic approach for kidney fibrosis.
