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

5 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

Funding Information:
Luminex assays were carried out in DartLab (A. Calkins) at the Immune Monitoring and Flow Cytometry Shared Resource at the Norris Cotton Cancer Center at Dartmouth, with NCI Cancer Center Support Grant 5P30 CA023108-37. RNA-sequencing experiments were carried out at Dartmouth Medical School in the Genomics Shared Resource (F. Kolling IV, Heidi Trask, and Elizabeth Sergison), which was established by equipment grants from the NIH and NSF and is supported in part by a Cancer Center Core Grant (P30CA023108) from the National Cancer Institute. Funding. Research was supported by NIH Grants No. R01AR070760 (RN), R01CA214062 (RN), 1R21CA227996- 01A1 (CC), RR180061 (CC), R01 HL56067 (BB), R01 HL 11879 (BB), and R37 AI34495 (BB) and Cancer Prevention and Research institute of Texas Grant No. RR180061 (CC).

Funding Information:
Research was supported by NIH Grants No. R01AR070760 (RN), R01CA214062 (RN), 1R21CA227996-01A1 (CC), RR180061 (CC), R01 HL56067 (BB), R01 HL 11879 (BB), and R37 AI34495 (BB) and Cancer Prevention and Research institute of Texas Grant No. RR180061 (CC).

Funding Information:
Luminex assays were carried out in DartLab (A. Calkins) at the Immune Monitoring and Flow Cytometry Shared Resource at the Norris Cotton Cancer Center at Dartmouth, with NCI Cancer Center Support Grant 5P30 CA023108-37. RNA-sequencing experiments were carried out at Dartmouth Medical School in the Genomics Shared Resource (F. Kolling IV, Heidi Trask, and Elizabeth Sergison), which was established by equipment grants from the NIH and NSF and is supported in part by a Cancer Center Core Grant (P30CA023108) from the National Cancer Institute.

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

Keywords

  • VISTA
  • agonist
  • immunosuppression
  • macrophage
  • tolerance

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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