Tamm-Horsfall Protein Regulates Granulopoiesis and Systemic Neutrophil Homeostasis

Abstract

Tamm-Horsfall protein (THP) is a glycoprotein uniquely expressed in the kidney. We recently showed an important role for THP in mediating tubular cross-talk in the outer medulla and in suppressing neutrophil infiltration after kidney injury. However, it remains unclear whether THP has a broader role in neutrophil homeostasis. In this study, we show that THP deficiency in mice increases the number of neutrophils, not only in the kidney but also in the circulation and in the liver, through enhanced granulopoiesis in the bone marrow. Using multiplex ELISA, we identified IL-17 as a key granulopoietic cytokine specifically upregulated in the kidneys but not in the liver of THP 2/2 mice. Indeed, neutralization of IL-17 in THP 2/2 mice completely reversed the systemic neutrophilia. Furthermore, IL-23 was also elevated in THP 2/2 kidneys. We performed real-time PCR on laser microdissected tubular segments and FACS-sorted renal immune cells and identified the S3 proximal segments, but not renal macrophages, as a major source of increased IL-23 synthesis. In conclusion, we show that THP deficiency stimulates proximal epithelial activation of the IL-23/IL-17 axis and systemic neutrophilia. Our findings provide evidence that the kidney epithelium in the outer medulla can regulate granulopoiesis. When this novel function is added to its known role in erythropoiesis, the kidney emerges as an important regulator of the hematopoietic system.

Tubular cross talk in acute kidney injury: a story of sense and sensibility

“…In fact, it was previously observed that mice deficient in THP exhibit a systemic inflammatory phenotype, marked by increased levels of several cytokines and chemokines in the blood (38). We observed recently that THPϪ/Ϫ mice have systemic neutrophilia caused by increased granulopoiesis in the bone marrow (41). This was caused by activation of the IL-23/IL-17 axis in the THPϪ/Ϫ kidneys.…”

“…4B) (16,18,25,41). The relative THP deficiency, seen in wild-type kidneys, may indeed be part of the pathophysiology of ischemic AKI (27).…”

“…IL-17 is a potent stimulator of other inflammatory cytokines and can induce systemic granulopoiesis through the production of granulocyte colonystimulating growth factor (1,29,(62)(63). To determine the source of IL-23 in THPϪ/Ϫ kidneys, we used real-time PCR on RNA extracted from various cell types in the kidney (epithelial and immune cells) using laser microdissection and FACS (41). Surprisingly, we found that S3 tubular segments, and not renal immune cells, were the source of IL-23.…”

“…In this model, S1 senses systemic danger as conveyed by information in the filtrate (31), whereas TAL is a sensor of endogenous kidney stress. This TAL function is facilitated by it spanning from the cortex to the medulla and regulating the level of THP (15,27,41). These sensor segments then activate the S2-S3 segments, which in turn shape the overall response of the kidney through the production of cytokines or chemokines (16,41).…”

“…This TAL function is facilitated by it spanning from the cortex to the medulla and regulating the level of THP (15,27,41). These sensor segments then activate the S2-S3 segments, which in turn shape the overall response of the kidney through the production of cytokines or chemokines (16,41). However, this process itself will also sensitize S2-S3 to injury (26,31).…”