VISTA deficiency protects from immune complex-mediated glomerulonephritis by inhibiting neutrophil activation

J Autoimmun. 2020 Sep;113:102501. doi: 10.1016/j.jaut.2020.102501. Epub 2020 Jun 22.

Abstract

V-type immunoglobulin domain-containing suppressor of T-cell activation (VISTA) is a negative checkpoint regulator of T cells. We assessed VISTA deficient mice in the murine nephrotoxic nephritis models of acute and chronic immune-complex mediated glomerulonephritis. We show that VISTA deficiency protects from crescentic glomerulonephritis, with no effect on the nephritogenic adaptive immune response. The early neutrophil influx was unaffected but proteinuria was reduced suggesting a reduction in neutrophil activation. In vivo, there was reduced neutrophil degranulation in VISTA deficienct mice and, in vitro, VISTA-deficient neutrophils had an impaired response to immune complexes but not to fMLP or PMA. Mice with a genetic deficiency of neutrophils due to myeloid-specific deletion of myeloid cell leukemia 1 (Mcl-1) were also protected from crescentic glomerulonephritis, indicating an essential role for neutrophils. Therefore, VISTA deficiency inhibits neutrophil activation by immune complexes and neutrophil-dependent crescentic glomerulonephritis. This suggests that VISTA is a therapeutic target for inflammatory disease. However, this would need to be balanced against a potential enhancing effect on autoimmunity.

Keywords: Glomerulonephritis; Immune complex; Inflammation; Neutrophil.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen-Antibody Complex / immunology*
  • Disease Models, Animal
  • Freund's Adjuvant / administration & dosage
  • Freund's Adjuvant / immunology
  • Glomerulonephritis / blood
  • Glomerulonephritis / immunology*
  • Glomerulonephritis / pathology
  • Humans
  • Kidney Glomerulus / immunology
  • Kidney Glomerulus / pathology*
  • Male
  • Membrane Proteins / deficiency*
  • Membrane Proteins / genetics
  • Mice
  • Mice, Transgenic
  • Myeloid Cell Leukemia Sequence 1 Protein / deficiency
  • Myeloid Cell Leukemia Sequence 1 Protein / genetics
  • Neutrophil Activation
  • Neutrophils / immunology*
  • Neutrophils / metabolism

Substances

  • Antigen-Antibody Complex
  • Mcl1 protein, mouse
  • Membrane Proteins
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Vsir protein, mouse
  • Freund's Adjuvant