PSTPIP2 ameliorates aristolochic acid nephropathy by suppressing interleukin-19-mediated neutrophil extracellular trap formation
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eLife assessment
This paper is of interest to a broad audience of cell biologists, and researchers who work in cell death and the role of NETosis in the pathogenesis of chronic diseases. This study presents valuable new insights to support NETosis plays an important role in the development of aristolochic acid nephropathy (AAN). A series of compelling experiments using in vivo and in vitro model supported that AAN induced NET formation via IL-19-IL20-beta receptor can induce inflammation and cell death. This new knowledge of the interaction between kidney cells and neutrophils could have clinical implications in the treatment of AAN.
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Abstract
Aristolochic acid nephropathy (AAN) is a progressive kidney disease caused by herbal medicines. Proline–serine–threonine phosphatase-interacting protein 2 (PSTPIP2) and neutrophil extracellular traps (NETs) play important roles in kidney injury and immune defense, respectively, but the mechanism underlying AAN regulation by PSTPIP2 and NETs remains unclear. We found that renal tubular epithelial cell (RTEC) apoptosis, neutrophil infiltration, inflammatory factor, and NET production were increased in a mouse model of AAN, while PSTPIP2 expression was low. Conditional knock-in of Pstpip2 in mouse kidneys inhibited cell apoptosis, reduced neutrophil infiltration, suppressed the production of inflammatory factors and NETs, and ameliorated renal dysfunction. Conversely, downregulation of Pstpip2 expression promoted kidney injury. In vivo, the use of Ly6G-neutralizing antibody to remove neutrophils and peptidyl arginine deiminase 4 (PAD4) inhibitors to prevent NET formation reduced apoptosis, alleviating kidney injury. In vitro, damaged RTECs released interleukin-19 (IL-19) via the PSTPIP2/nuclear factor (NF)-κB pathway and induced NET formation via the IL-20Rβ receptor. Concurrently, NETs promoted apoptosis of damaged RTECs. PSTPIP2 affected NET formation by regulating IL-19 expression via inhibition of NF-κB pathway activation in RTECs, inhibiting RTEC apoptosis, and reducing kidney damage. Our findings indicated that neutrophils and NETs play a key role in AAN and therapeutic targeting of PSTPIP2/NF-κB/IL-19/IL-20Rβ might extend novel strategies to minimize Aristolochic acid I-mediated acute kidney injury and apoptosis.
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eLife assessment
This paper is of interest to a broad audience of cell biologists, and researchers who work in cell death and the role of NETosis in the pathogenesis of chronic diseases. This study presents valuable new insights to support NETosis plays an important role in the development of aristolochic acid nephropathy (AAN). A series of compelling experiments using in vivo and in vitro model supported that AAN induced NET formation via IL-19-IL20-beta receptor can induce inflammation and cell death. This new knowledge of the interaction between kidney cells and neutrophils could have clinical implications in the treatment of AAN.
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Reviewer #1 (Public Review):
The author tried to figure out whether neutrophil extracellular traps are involved in aristolochic acid nephropathy. Overall, this study provided some novel findings to support the conclusion. But the generation of knockin mice, IL-19 function in vivo, and the underlying mechanism by which PSTPIP2 influences NF-KB-IL-19 need to be further clarified.
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Reviewer #2 (Public Review):
This study by Du et. al addressed the role and regulation of proline-serine-threonine phosphatase interacting protein 2 (PSTPIP2) and neutrophil extracellular traps (NETs) in Aristolochic acid Nephropthathy (AAN) and immune defense. PSTPIP2 expression is downregulated in AAN. Conditional knock-in of PSTPIP2 in mouse kidneys inhibited cell apoptosis, reduced neutrophil infiltration, suppressed the production of inflammatory factors and NETs, and ameliorated renal dysfunction. Reducing the expression of PSTPIP2 to normal levels in knock-in mouse using shRNA promoted kidney injury. Using in vivo model, the role of PSTPIP2 in AAN injury and renal function, apoptosis, neutrophil infiltration and NET formation is established. Using in vitro models, a PSTPIP2/NFkB-mediated NET formation via IL-19-IL20-beta Receptor …
Reviewer #2 (Public Review):
This study by Du et. al addressed the role and regulation of proline-serine-threonine phosphatase interacting protein 2 (PSTPIP2) and neutrophil extracellular traps (NETs) in Aristolochic acid Nephropthathy (AAN) and immune defense. PSTPIP2 expression is downregulated in AAN. Conditional knock-in of PSTPIP2 in mouse kidneys inhibited cell apoptosis, reduced neutrophil infiltration, suppressed the production of inflammatory factors and NETs, and ameliorated renal dysfunction. Reducing the expression of PSTPIP2 to normal levels in knock-in mouse using shRNA promoted kidney injury. Using in vivo model, the role of PSTPIP2 in AAN injury and renal function, apoptosis, neutrophil infiltration and NET formation is established. Using in vitro models, a PSTPIP2/NFkB-mediated NET formation via IL-19-IL20-beta Receptor pathway is shown to induce inflammation and apoptosis in AAN. The studies are well presented.
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