AUTHOR=ElTanbouly Mohamed A. , Schaafsma Evelien , Smits Nicole C. , Shah Parth , Cheng Chao , Burns Christopher , Blazar Bruce R. , Noelle Randolph J. , Mabaera Rodwell TITLE=VISTA Re-programs Macrophage Biology Through the Combined Regulation of Tolerance and Anti-inflammatory Pathways JOURNAL=Frontiers in Immunology VOLUME=11 YEAR=2020 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.580187 DOI=10.3389/fimmu.2020.580187 ISSN=1664-3224 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.