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Abstract: PO1761

IL233-Induced Remission from Lupus Glomerulonephritis Involves Regulation of Mitochondrial Function and Canonical WNT Signaling

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • Venkatadri, Rajkumar, University of Virginia, Charlottesville, Virginia, United States
  • Sabapathy, Vikram, University of Virginia, Charlottesville, Virginia, United States
  • Dogan, Murat, University of Virginia, Charlottesville, Virginia, United States
  • Mohammad, Saleh, University of Virginia, Charlottesville, Virginia, United States
  • Fu, Shu man, University of Virginia, Charlottesville, Virginia, United States
  • Sharma, Rahul, University of Virginia, Charlottesville, Virginia, United States
Background

We recently showed the efficacy of a hybrid cytokine IL233 to protect mice from lupus glomerulonephritis (GN). We have now investigated the status of mitochondrial function, canonical Wnt signaling and metabolic fitness of regulatory T cells (Tregs), risk factors known to be associated with lupus GN to further delineate the mechanisms of protection offered by IL233.

Methods

We made use of the recombinant hybrid cytokine (IL233) bearing activities of IL-2 and IL-33 and tested its efficacy to prevent glomerular nephritis in the adenovirus (Ad)IFNa accelerated lupus GN NZM2328 model. Kidney lysates were screened for transcripts of mitochondrial and Wnt inhibitor genes by real time PCR and Western blotting. Mitochondrial membrane potential and metbolic fitness in IL233 treated mouse glomerular endothelial cells (MGECs) was investigated by flow cytometry and Seahorse assay. Metabolic fitness of Tregs with and without IL233 treatments were investigated by Seahorse assay by employing ex vivo and in vivo approaches.

Results

Analysis of transcript levels of mitochondrial function and biogenesis related genes (Pgc1α, Nrf1, Nrf2, Tfam, Drp1 and Mfn1) confirmed that IL233 treated kidneys displayed an elevated status. In vitro, changes in Pgc1α and its downstream target Nrf2 were recapitulated in treated MGEC cells. IL233 treated Tregs (ex vivo and in vivo) and MGECs (in vitro) also exhibited better mitochondrial metabolic fitness and displayed elevated levels of basal respiration, maximal respiration and ATP production investigated by the Seahorse assay. Wnt activators LRP6, Dvl3 and Wnt mediators - Axin1, GSK3a and GSK3b were significantly reduced in IL233 protected kidney. Levels of Axin2 was significantly upregulated with IL233 treatment indicating activation of a negative feedback loop for Wnt inhibition.

Conclusion

We present in depth mechanistic evidence of the observed remission from lupus GN with IL233 treatment. IL233 treated kidneys exhibit better mitochondrial dynamics and function. We show in vitro, in vivo and ex vivo evidence of IL233 treatment leading to betterment of mitochondrial function and metabolic fitness. Canonical Wnt signaling was attenuated. The data presented confirms the therapeutic efficacy of IL233 as a promising therapeutic agent for lupus nephritis and kidney injury.

Funding

  • Other NIH Support