Tumor Necrosis Factor-Alpha Antagonist Interferes With the Formation of Granulomatous Multinucleated Giant Cells: New Insights Into Mycobacterium tuberculosis Infection.

Soraya Mezouar,Jean Roudier,Jean-Louis Mege,Issa Diarra,Benoit Desnues

doi:10.3389/fimmu.2019.01947

Abstract

More than half of tuberculosis cases in the world are due to resuscitation of dormant Mycobacterium tuberculosis (Mtb) sequestered into cell-derived structures called granulomas. It is fairly admitted that cytokines and more particularly Tumor Necrosis Factor (TNF)-α is critical in the control of Mtb infections and that anti-TNF-α drugs constitute one of the main risk factors for reactivation of latent Mtb infection. The aim of this study was to evaluate the role of etanercept, a dimeric fusion protein consisting of the extracellular ligand-binding portion of the human p75 TNF receptor linked to the Fc portion of human IgG1, in an in vitro model of human tuberculous granuloma. We showed that etanercept slightly delayed the formation of granuloma and reduced the generation of multinuclear giant cells (MGCs). In addition, etanercept exacerbated the expression of M1 polarization genes but also induced interleukin (IL)-10 release. In addition, our results indicated that etanercept inhibited cell fusion in an IL-10-dependent manner. Moreover, adalimumab, a human monoclonal anti-TNF-α IgG1 inhibited MGC formation in granuloma, without altering IL-10 secretion and induced macrophage apoptosis. Taken together, our data provides new insights into the role of TNF-α blockers in MGCs formation and the impact of such immunomodulatory drugs on tuberculous granuloma maturation.

Highlights

Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis (Mtb), which remains a major threat in terms of mortality and morbidity
peripheral blood mononuclear cells (PBMCs) from healthy donors were incubated with Mtb extractcoated beads in the presence or not of etanercept and granuloma formation was followed over time
Granuloma formation is the key response of immune cells against Mtb infection

Summary

Introduction

Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis (Mtb), which remains a major threat in terms of mortality and morbidity. While nearly one fourth of the global population is latently infected by Mtb (1.7 billion individuals), only 5–10% of infected people develop active tuberculosis [1]. Most exposed individuals remain asymptomatic and are referred as Multinucleated Giant Cells in Tuberculosis Infection latent tuberculosis individuals [2]. Infection of macrophages and dendritic cells by Mtb leads to T cell activation and cytokine production [4, 5], among which interleukin (IL)-12 and interferon (IFN)-γ have been shown essential for the protection against Mtb as revealed by murine models and human immune deficiencies [3]. Among cytokines secreted by Mtb-activated immune cells and infected individuals, tumor necrosis factor (TNF)-α has been considered as necessary for bacterial killing [6]

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