Myeloid cell TNFR1 signaling dependent liver injury and inflammation upon BCG infection

Leslie Chavez-Galan,Stéphanie Rose,Valérie F J Quesniaux,Dominique Vesin,Sulayman Benmerzoug,Irene Garcia,Husnu Uysal,Guillaume Blaser,Bernhard Ryffel

doi:10.1038/s41598-019-41629-9

Abstract

TNF plays a critical role in mononuclear cell recruitment during acute Bacillus Calmette-Guérin (BCG) infection leading to an effective immune response with granuloma formation, but may also cause tissue injury mediated by TNFR1 or TNFR2. Here we investigated the role of myeloid and T cell specific TNFR1 and R2 expression, and show that absence of TNFR1 in myeloid cells attenuated liver granuloma formation and liver injury in response to acute BCG infection, while TNFR2 expressed in myeloid cells contributed only to liver injury. TNFR1 was the main receptor controlling cytokine production by liver mononuclear cells after antigenic specific response, modified CD4/CD8 ratio and NK, NKT and regulatory T cell recruitment. Further analysis of CD11b+CD3+ phagocytic cells revealed a TCRαβ expressing subpopulation of unknown function, which increased in response to BCG infection dependent of TNFR1 expression on myeloid cells. In conclusion, TNFR1 expressed by myeloid cells plays a critical role in mononuclear cell recruitment and injury of the liver after BCG infection.

Highlights

Bacillus Calmette-Guérin (BCG) is a live attenuated Mycobacterium bovis, which is currently used as vaccine against Mycobacterium tuberculosis (M.tuberculosis) infection
To assess the relative contribution of the cell specific TNFRs expression on cell recruitment to the liver during the early responses to intravenous BCG infection, WT, TNF receptor 1 (TNFR1) KO, TNFR1-M KO, TNFR1-T KO, TNF receptor 2 (TNFR2) Flox, TNFR2-M KO and TNFR2-T KO mice were infected with living BCG and liver analyzed at 2-weeks post-infection
Cell specific deficiency of TNFR2 did not influence significantly granuloma number and size as compared to TNFR2 Flox mice (Fig. 1h–j). These data show that after BCG-infection, TNFR1 on myeloid or lymphoid cells plays a predominant role to control both liver inflammation and granuloma formation, but TNFR2 expressed on myeloid cells only contributes to hepatotoxicity

Summary

Introduction

Bacillus Calmette-Guérin (BCG) is a live attenuated Mycobacterium bovis, which is currently used as vaccine against Mycobacterium tuberculosis (M.tuberculosis) infection. BCG activates TNF production, which is one important proinflammatory cytokine required for protection against mycobacteria while TNF is involved in mycobacterial-induced liver injury. To investigate how the absence of TNFR1 or TNFR2 expression on myeloid and lymphoid cells influences liver cell recruitment during acute BCG infection and their potential hepatotoxicity, we have used a genetic approach with mice bearing a specific deletion of TNFR1 on myeloid (TNFR1-M KO) or on T cells (TNFR1-T KO). TNFR1 deficiency affects the recruitment of both myeloid and lymphoid cells, including the presence and activity of CD3+ myeloid cells already described in BCG granulomas[19]. Myeloid or lymphoid TNFR2 depletion affects marginally hepatic cell recruitment but causes changes in cell function during BCG infection. Myeloid cells expressing either TNFR1 or TNFR2 contribute to liver injury

Methods

Results

Conclusion