HIV-1 Envelope Glycoproteins Induce the Production of TNF-\u03b1 and IL-10 in Human Monocytes by Activating Calcium Pathway

Rémi Planès,Elmostafa Bahraoui,Kaoutar Leghmari,Lbachir BenMohamed,Manutea Serrero

doi:10.1038/s41598-018-35478-1

Abstract

Human HIV-1 infection leads inevitably to a chronic hyper-immune-activation. However, the nature of the targeted receptors and the pathways involved remain to be fully elucidated. We demonstrate that X4-tropic gp120 induced the production of TNF-α and IL-10 by monocytes through activation of a cell membrane receptor, distinct from the CD4, CXCR4, and MR receptors. Gp120 failed to stimulate IL-10 and TNF-α production by monocytes in Ca2+ free medium. This failure was total for IL-10 and partial for TNF-α. However, IL-10 and TNF-α production was fully restored following the addition of exogenous calcium. Accordingly, addition of BAPTA-AM and cyclosporine-A, fully and partially inhibited IL-10 and TNF-α respectively. The PKA pathway was crucial for IL-10 production but only partially involved in gp120-induced TNF-α. The PLC pathway was partially and equivalently involved in gp120-induced TNF-α and IL-10. Moreover, the inhibition of PI3K, ERK1/2, p38 MAP-kinases and NF-κB pathways totally abolished the production of both cytokines. In conclusion, this study revealed the crucial calcium signaling pathway triggered by HIV-1 gp120 to control the production of these two cytokines: TNF-α and IL-10. The finding could help in the development of a new therapeutic strategy to alleviate the chronic hyper-immune-activation observed in HIV-1 infected patients.

Highlights

Besides TNF-α, the IL-10, a highly immunosuppressive cytokine, seems to play a key role in HIVassociated immune dysregulation[12,13,14]
We demonstrate that the HIV-1 gp[120] stimulated the production of both TNF-α and IL-10 in human monocytes, in a CD4 and CCR5/CXCR4 independent manner, by recruiting selective, specific and common pathways
We demonstrate that calcium and PKA pathways are essential for IL-10, but not for TNF-α production by monocytes stimulated by gp[120], while PI3K, ERK1/2 and P38 MAP kinases, and NF-κB are essential for the production of both TNF-α and IL-10

Summary

Introduction

Besides TNF-α, the IL-10, a highly immunosuppressive cytokine, seems to play a key role in HIVassociated immune dysregulation[12,13,14]. Progressors[12,13,14]; (ii) patients producing less IL-10, due to the mutation IL-10–5′–592A on the IL-10 promoter, evolve less rapidly to the AIDS stage[15]; (iii) elite controllers, who do not develop AIDS diseases despite their seropositive status, do not show an increase in IL-1016; and (iv) in patients receiving effective anti-retroviral therapy, plasmatic IL-10 level decreases in parallel with the decrease in viral load[16] In line with these observations, in-vitro studies have shown that IL-10 is directly involved in the loss of immune system function and immune-pathology. In addition to mediate productive viral infection following interaction with CD4, CCR5 and CXCR4, the gp[120] bind to several other receptors expressed by non-permissive cells including integrin α4β739, C-type lectin DC-SIGN40, the mannose receptor MR22, TLR2, and TLR441. We demonstrate that calcium and PKA pathways are essential for IL-10, but not for TNF-α production by monocytes stimulated by gp[120], while PI3K, ERK1/2 and P38 MAP kinases, and NF-κB are essential for the production of both TNF-α and IL-10

Methods

Results

Conclusion