The C-Type Lectin Receptor DC-SIGN Has an Anti-Inflammatory Role in Human M(IL-4) Macrophages in Response to Mycobacterium tuberculosis

Frontiers in Immunology

Ivanela Kondova¹  Frank A. W. Verreck¹  Claire Lastrucci²  Alan Bénard³  Maria del Carmen Sasiain⁴  Luciana Balboa⁴  Florence Capilla⁵  Talal Al Saati⁵  Renaud Poincloux⁶  Carine Duval⁶  Ingrid Mercier⁶  Céline Cougoule⁷  Isabelle Maridonneau-Parini⁷  Geanncarlo Lugo-Villarino⁷  Olivier Neyrolles⁷  Anthony Troegeler⁷ 

[1] Biomedical Primate Research Centre, Rijswijk, Netherlands;Centre for Genomic Regulation, Barcelona, Spain;Department of Surgery, University, Hospital Erlangen, Friedrich-Alexander, University Erlangen-Nürnberg, Erlangen, Germany;IMEX-CONICET, Academia Nacional de Medicina, Buenos Aires, Argentina;INSERM/UPS/US006 CREFRE, CHU Purpan, Toulouse, France;Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France;International Associated Laboratory (LIA) CNRS “IM–TB/HIV” (1167), Buenos Aires, Argentina;International Associated Laboratory (LIA) CNRS “IM–TB/HIV” (1167), Toulouse, France;

关键词: macrophages;    Mycobacterium tuberculosis;    DC-SIGN;    C-type lectin receptors;    anti-inflammatory;   

DOI  :  10.3389/fimmu.2018.01123

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown