The C-Type lectin receptor DC-SIGN has an anti-inflammatory role in human M(IL-4) macrophages in response to Mycobacterium tuberculosis

Lugo-Villarino, Geanncarlo; Troegeler, Anthony; Balboa, Luciana; Lastrucci, Claire; Duval, Carine; Mercier, Ingrid; Bénard, Alan; Capilla, Florence; Al Saati, Talal; Poincloux, Renaud; Kondova, Ivanela; Verreck, Frank A. W.; Cougoule, Céline; Maridonneau-Parini, Isabelle; Sasiain, Maria del Carmen; Neyrolles, Olivier

doi:http://dx.doi.org/10.3389/fimmu.2018.01123

The C-Type lectin receptor DC-SIGN has an anti-inflammatory role in human M(IL-4) macrophages in response to Mycobacterium tuberculosis

Citation

Lugo-Villarino G, Troegeler A, Balboa L, Lastrucci C, Duval C, Mercier I, Bénard A, Capilla F, Al Saati T, Poincloux R, Kondova I, Verreck FAW, Cougoule C, Maridonneau-Parini I, Sasiain MDC, Neyrolles O. The C-Type lectin receptor DC-SIGN has an anti-inflammatory role in human M(IL-4) macrophages in response to Mycobacterium tuberculosis. Front Immunol. 2018; 9:1123. DOI 10.3389/fimmu.2018.01123

Abstract

DC-SIGN (CD209/CLEC4L) is a C-type lectin receptor (CLR) that serves as a reliable cell-surface marker of interleukin 4 (IL-4)-activated human macrophages [M(IL-4)], which historically represent the most studied subset within the M2 spectrum of macrophage activation. Although DC-SIGN plays important roles in Mycobacterium tuberculosis (Mtb) interactions with dendritic cells, its contribution to the Mtb-macrophage interaction remains poorly understood. Since high levels of IL-4 are correlated with tuberculosis (TB) susceptibility and progression, we investigated the role of DC-SIGN in M(IL-4) macrophages in the TB context. First, we demonstrate that DC-SIGN expression is present both in CD68+ macrophages found in tuberculous pulmonary lesions of non-human primates, and in the CD14+ cell population isolated from pleural effusions obtained from TB patients (TB-PE). Likewise, we show that DC-SIGN expression is accentuated in M(IL-4) macrophages derived from peripheral blood CD14+ monocytes isolated from TB patients, or in macrophages stimulated with acellular TB-PE, arguing for the pertinence of DC-SIGN-expressing macrophages in TB. Second, using a siRNA-mediated gene silencing approach, we performed a transcriptomic analysis of DC-SIGN-depleted M(IL-4) macrophages and revealed the upregulation of pro-inflammatory signals in response to challenge with Mtb, as compared to control cells. This pro-inflammatory gene signature was confirmed by RT-qPCR, cytokine/chemokine-based protein array, and ELISA analyses. We also found that inactivation of DC-SIGN renders M(IL-4) macrophages less permissive to Mtb intracellular growth compared to control cells, despite the equal level of bacteria uptake. Last, at the molecular level, we show that DC-SIGN interferes negatively with the pro-inflammatory response and control of Mtb intracellular growth mediated by another CLR, Dectin-1 (CLEC7A). Collectively, this study highlights a dual role for DC-SIGN as, on the one hand, being a host factor granting advantage for Mtb to parasitize macrophages and, on the other hand, representing a molecular switch to turn off the pro-inflammatory response in these cells to prevent potential immunopathology associated to TB.