SerpinB2 Regulates Immune Response in Kidney Injury and Aging
- 1 May 2020
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Journal of the American Society of Nephrology
- Vol. 31 (5), 983-995
- https://doi.org/10.1681/ASN.2019101085
Abstract
Significance StatementInjured tubular cells activate a kidney survival program that includes complex crosstalk between tubular cells and macrophages. The authors show that SerpinB2, known to be expressed in activated macrophages, is also upregulated in stressed tubular cells. By subjecting knockout mice lacking SerpinB2 to renal stress, they show that SerpinB2 promotes proreparative adaptation of the kidney by two cell type?specific mechanisms: it enhances expression of the chemokine CCL2 in tubular cells, which supports transient intrarenal leukocyte accumulation, and it regulates function of macrophages by activating phagocytosis and inhibiting migration. These functions are crucial for timely resolution of inflammation, successful repair, and kidney homeostasis during aging. These findings suggest that SerpinB2 merits further exploration for its role in the human kidney in acute and chronic disease. BackgroundExpression of SerpinB2, a regulator of inflammatory processes, has been described in the context of macrophage activation and cellular senescence. Given that mechanisms for these processes interact and can shape kidney disease, it seems plausible that SerpinB2 might play a role in renal aging, injury, and repair.MethodsWe subjected SerpinB2 knockout mice to ischemia-reperfusion injury or unilateral ureteral obstruction. We performed phagocyte depletion to study SerpinB2?s role beyond the effects of macrophages and transplanted bone marrow from knockout mice to wild-type mice and vice versa to dissect cell type?dependent effects. Primary tubular cells and macrophages from SerpinB2 knockout and wild-type mice were used for functional studies and transcriptional profiling.ResultsCultured senescent tubular cells, kidneys of aged mice, and renal stress models exhibited upregulation of SerpinB2 expression. Functionally, lack of SerpinB2 in aged knockout mice had no effect on the magnitude of senescence markers but associated with enhanced kidney damage and fibrosis. In stress models, inflammatory cell infiltration was initially lower in knockout mice but later increased, leading to an accumulation of significantly more macrophages. SerpinB2 knockout tubular cells showed significantly reduced expression of the chemokine CCL2. Macrophages from knockout mice exhibited reduced phagocytosis and enhanced migration. Macrophage depletion and bone marrow transplantation experiments validated the functional relevance of these cell type?specific functions of SerpinB2.ConclusionsSerpinB2 influences tubule-macrophage crosstalk by supporting tubular CCL2 expression and regulating macrophage phagocytosis and migration. In mice, SerpinB2 expression seems to be needed for coordination and timely resolution of inflammation, successful repair, and kidney homeostasis during aging. Implications of SerpinB2 in human kidney disease deserve further exploration.Funding Information
- German Research Foundation (SCHM 2146/6-1, SFB738)
- Dr. Werner Jackstädt Stiftung
- Salisbury Cove Research Fund at I Biological Laboratory
- Hannover Biomedical Research School
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