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

VISTA deficiency protects from immune complex-mediated glomerulonephritis by inhibiting neutrophil activation
VISTA deficiency protects from immune complex-mediated glomerulonephritis by inhibiting neutrophil activation
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 deficiency 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 neutrophildependent 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
0896-8411
Cragg, Mark
ec97f80e-f3c8-49b7-a960-20dff648b78c
Cragg, Mark
ec97f80e-f3c8-49b7-a960-20dff648b78c

Cragg, Mark (2020) VISTA deficiency protects from immune complex-mediated glomerulonephritis by inhibiting neutrophil activation. Journal of Autoimmunity, [102501]. (doi:10.1016/j.jaut.2020.102501).

Record type: Article

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 deficiency 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 neutrophildependent 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

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Accepted/In Press date: 31 May 2020
e-pub ahead of print date: 22 June 2020

Identifiers

Local EPrints ID: 442227
URI: http://eprints.soton.ac.uk/id/eprint/442227
ISSN: 0896-8411
PURE UUID: 08506736-6e1d-4579-8758-41fb959a9660
ORCID for Mark Cragg: ORCID iD orcid.org/0000-0003-2077-089X

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Date deposited: 09 Jul 2020 16:31
Last modified: 26 Nov 2021 06:16

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