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

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

doi:10.3389/fimmu.2020.580187

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.

Highlights

Macrophage plasticity plays an important role in controlling both the amplitude and quality of the inflammatory response in a wide variety of physiological and pathological conditions, as well as the resolution of inflammation and tissue repair
Based on prior studies that showed that anti-V-domain Ig suppressor of T cell activation (VISTA) could diminish innate inflammation, initial studies were designed to determine if anti-VISTA could enhance LPS tolerance
These findings show that anti-VISTA synergizes with low dose LPS to expand a program that reduces the production of proinflammatory cytokines

Summary

Introduction

Macrophage plasticity plays an important role in controlling both the amplitude and quality of the inflammatory response in a wide variety of physiological and pathological conditions, as well as the resolution of inflammation and tissue repair. Macrophages undergo extensive transcriptional and epigenetic reprogramming in response to various environmental cues. These cues allow macrophages to rapidly respond to danger signals by inducing pro-inflammatory mediators on one extreme or to exist in a regulatory state for the purpose of tissue repair and/or maintenance. Lipopolysaccharide (LPS) tolerance is an example of transcriptional and epigenetic reprogramming that prevents macrophage overactivation through development of refractoriness to repeated stimulation resulting in reduced capacity of macrophages to mediate septic shock. LPS tolerance has been extensively studied in vivo and in vitro with well-documented changes in transcriptional and epigenetic landscapes that abrogates release of the prototypic inflammatory cytokines secreted by activated macrophages, including TNFα, IL-6, IL-1, and IL-12p40. Several mediators including IRAK-M [3], NF-κB1 (p50) [4, 5], mir221/222 [6], IRG1, and A20 [7] have been implicated in mediating or enhancing LPS tolerance

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Conclusion