VISTA Re-programs Macrophage Biology Through the Combined Regulation of Tolerance and Anti-inflammatory Pathways

Mohamed A. ElTanbouly, Evelien Schaafsma, Nicole C. Smits, Parth Shah, Chao Cheng, Christopher Burns, Bruce R. Blazar, Randolph J. Noelle, Rodwell Mabaera

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

We present the novel finding that V-domain Ig suppressor of T cell activation (VISTA) negatively regulates innate inflammation through the transcriptional and epigenetic re-programming of macrophages. Representative of VISTA re-programming is the ability of VISTA agonistic antibodies to augment LPS tolerance and reduce septic shock lethality in mice. This anti-inflammatory effect of anti-VISTA was mimicked in vitro demonstrating that anti-VISTA treatment caused a significant reduction in LPS-induced IL-12p40, IL-6, CXCL2, and TNF; all hallmark pro-inflammatory mediators of endotoxin shock. Even under conditions that typically “break” LPS tolerance, VISTA agonists sustained a macrophage anti-inflammatory profile. Analysis of the proteomic and transcriptional changes imposed by anti-VISTA show that macrophage re-programming was mediated by a composite profile of mediators involved in both macrophage tolerance induction (IRG1, miR221, A20, IL-10) as well as transcription factors central to driving an anti-inflammatory profile (e.g., IRF5, IRF8, NFKB1). These findings underscore a novel and new activity of VISTA as a negative checkpoint regulator that induces both tolerance and anti-inflammatory programs in macrophages and controls the magnitude of innate inflammation in vivo.

Original languageEnglish (US)
Article number580187
JournalFrontiers in immunology
Volume11
DOIs
StatePublished - Oct 15 2020

Bibliographical note

Publisher Copyright:
© Copyright © 2020 ElTanbouly, Schaafsma, Smits, Shah, Cheng, Burns, Blazar, Noelle and Mabaera.

Keywords

  • VISTA
  • agonist
  • immunosuppression
  • macrophage
  • tolerance

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