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.
Highlights
According to the latest World Health Organization (WHO) report, tuberculosis (TB) is the largest killer among communicable diseases (WHO Annual report 2017)
In samples from non-human primates (NHP) exhibiting a low pathological score in lungs, immunohistochemical analyses revealed the low presence of CD68+ macrophages and DC-SIGN-expressing cells in areas where leukocyte infiltrate was detected by hematoxylin and eosin (HE) staining (Figure 1A)
To determine whether DC-SIGN is expressed by M2 macrophages in the context of tuberculous granulomas, we performed an additional staining for CD163 and MerTK, two strong markers of M2 macrophages
Summary
According to the latest World Health Organization (WHO) report, tuberculosis (TB) is the largest killer among communicable diseases (WHO Annual report 2017). In 2016, there were an estimated 1.7 million deaths due to TB, making it the leading cause of death worldwide due to a single infectious agent, Mycobacterium tuberculosis (Mtb). It is estimated that one quarter of the human population could be latently infected with Mtb [1]. For which there are no pathological or contagious conditions, Mtb is contained within elaborated aggregates of immune cells that are called granulomas, the hallmark of TB [2, 3]. There is a strong need to better understand the factors that define an efficient immune response both during the early and late phases of Mtb infection in order to facilitate potential targets for preventive and therapeutic purposes
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