Farnesoid X receptor prevents neutrophil extracellular traps via reduced sphingosine-1-phosphate in chronic kidney disease

Bryce A. Jones, Komuraiah Myakala, Mahilan Guha, Shania Davidson, Sharmila Adapa, Isabel Lopez Santiago, Isabel Schaffer, Yang Yue, Jeremy C. Allegood, L. Ashley Cowart, Xiaoxin X. Wang, Avi Z. Rosenberg, Moshe Levi

Research output: Contribution to journalArticlepeer-review

Abstract

Farnesoid X receptor (FXR) activation reduces renal inflammation, but the underlying mechanisms remain elusive. Neutrophil extracellular traps (NETs) are webs of DNA formed when neutrophils undergo specialized programmed cell death (NETosis). The signaling lipid sphingosine-1-phosphate (S1P) stimulates NETosis via its receptor on neutrophils. Here, we identify FXR as a negative regulator of NETosis via repressing S1P signaling. We determined the effects of the FXR agonist obeticholic acid (OCA) in mouse models of adenosine phosphoribosyltransferase (APRT) deficiency and Alport syndrome, both genetic disorders that cause chronic kidney disease. Renal FXR activity is greatly reduced in both models, and FXR agonism reduces disease severity. Renal NETosis and sphingosine kinase 1 (Sphk1) expression are increased in diseased mice, and they are reduced by OCA in both models. Genetic deletion of FXR increases Sphk1 expression, and Sphk1 expression correlates with NETosis. Importantly, kidney S1P levels in Alport mice are two-fold higher than controls, and FXR agonism restores them back to baseline. Short-term inhibition of sphingosine synthesis in Alport mice with severe kidney disease reverses NETosis, establishing a causal relationship between S1P signaling and renal NETosis. Finally, extensive NETosis is present in human Alport kidney biopsies (six male, nine female), and NETosis severity correlates with clinical markers of kidney disease. This suggests the potential clinical relevance of the newly identified FXR-S1P-NETosis pathway. In summary, FXR agonism represses kidney Sphk1 expression. This inhibits renal S1P signaling, thereby reducing neutrophilic inflammation and NETosis.

Original languageEnglish (US)
Pages (from-to)F792-F810
JournalAmerican Journal of Physiology - Renal Physiology
Volume325
Issue number6
DOIs
StatePublished - Dec 2023

Keywords

  • Alport syndrome
  • NETosis
  • adenine diet
  • farnesoid X receptor
  • sphingosine-1-phosphate

ASJC Scopus subject areas

  • Urology
  • Physiology

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