Regulatory B Cell-Targeted Therapeutic Interventions Against AKI-to-CKD Transition

Background: Acute kidney injury (AKI) occurs in 20% of hospitalized patients and predisposes the patients to chronic kidney disease (CKD). B cells presenting with CD1dhiCD5+ are recognized as regulatory B cells (Bregs), which can produce and secrete interleukin-10 (IL-10). IL-10 is an anti-inflammatory cytokine and its administration has shown renoprotective effects against AKI. However, a large amount of IL-10 would be required to reach therapeutic concentrations in humans. To explore the potential of Bregs as a therapeutic strategy, we investigated how AKI affects Breg proliferation and examined whether Bregs infusion and in vivo induction prevent AKI-to-CKD transition. Methods: IL10+/eGFP mice were employed to track IL-10-producing Bregs in ischemic reperfusion (IR)-AKI and GFP+ Bregs were quantified in organs, including kidney and spleen at different time points. B1a cells, a major population of IL-10-producing B cells, were isolated from IL10+/eGFP mice and transferred into wild-type mice subject to IR-AKI to assess their renal infiltration and reno-protective effects. To explore whether deletion of splenic Bregs exacerbates the AKI-to-CKD, splenectomy was performed. Additionally, to evaluate in vivo induction of Bregs, we performed vagus nerve stimulation (VNS) before IR-AKI. Results: Splenic GFP+ Bregs markedly increased at 24 hours following IR-AKI, whereas renal GFP+ Bregs accumulated on day 7 and 14 after IR-AKI in parallel with increased IL-10 gene expression. Adoptive transfer of GFP+B1a cells led to enhanced accumulation of GFP+ cells in both the spleen and injured kidneys of wild-type mice compared to the uninjured controls. Splenectomy prior to IR-AKI reduced the number of GFP+ Bregs in the AKI kidneys accompanied by the decrease in renal IL-10. Splenic Bregs deficiency worsened tubular injury and kidney fibrosis with the increase in cytotoxic immune cells infiltration. Furthermore, VNS prior to IR-AKI promoted splenic B cells expansion and increased GFP+ Bregs in the AKI kidneys, and improved tubular injury, immune cells activation, and kidney fibrosis. Conclusion: Splenic Bregs are involved in proper kidney repair via promoting immune tolerance and attenuating tubular injury and fibrosis following IR-AKI. Adoptive transfusion with autologous Bregs or in vivo induction of Breg represents a potent therapeutic strategy to prevent the AKI-to-CKD.