Impact Factor 6.429

The 5th most cited journal in Immunology

Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2018.00272

Extracellular vesicles released from Mycobacterium tuberculosis-infected neutrophils promote macrophage autophagy and decrease intracellular mycobacterial survival

  • 1Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico
  • 2Departamento de Fisiología y Farmacología, Facultad de Medicina Veterinaria y Zootecnia, Universidad Nacional Autónoma de México, Mexico
  • 3Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Mexico
  • 4Laboratorio de Citometría de Flujo de Diagnóstico Molecular de Leucemias y Terapia Celular SA. De CV. (DILETEC), Mexico
  • 5Laboratorios Nacionales de Servicios Experimentales (LANSE), Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Mexico
  • 6Departamento de Bioquímica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico
  • 7Departamento de Biomedicina Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico
  • 8Unidad de Desarrollo e Investigación en Bioprocesos, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico

Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis (Mtb). In the lungs, macrophages and neutrophils are the first immune cells that have contact with the infecting mycobacteria. Neutrophils are phagocytic cells that kill microorganisms through several mechanisms, which include the lytic enzymes and antimicrobial peptides that are found in their lysosomes, and the production of reactive oxygen species (ROS). Neutrophils also release extracellular vesicles (EVs) (100 to 1,000 nm in diameter) to the extracellular milieu; these EVs consist of a lipid bilayer surrounding an hydrophilic core and participate in intercellular communication. We previously demonstrated that human neutrophils infected in vitro with Mtb H37Rv release EVs (EV-TB), but the effect of these EVs on other cells relevant for the control of Mtb infection, such as macrophages, has not been completely analyzed. In this study, we characterized the EVs produced by non-stimulated human neutrophils (EV-NS), and the EVs produced by neutrophils stimulated with an activator (PMA), a peptide derived from bacterial proteins (fMLF) or Mtb, and observed that the four EVs differed in their size. Ligands for TLR2/6 were detected in EV-TB, and these EVs favored a modest increase in the expression of the co‐stimulatory molecules CD80, a higher expression of CD86, and the production of higher amounts of TNF‐α and IL‐6, and of lower amounts of TGF‐β, in autologous human macrophages, compared to the other EVs. EV‐TB reduced the amount of intracellular Mtb in macrophages, and increased superoxide anion production in these cells. TLR2/6 ligation and superoxide anion production are known inducers of autophagy; accordingly, we found that EV-TB induced higher expression of the autophagy-related marker LC3-II in macrophages, and the co-localization of LC3-II with Mtb inside infected macrophages. The intracellular mycobacterial load increased when autophagy was inhibited with wortmannin in these cells. In conclusion, our results demonstrate that neutrophils produce different EVs in response to diverse activators, and that EV-TB activate macrophages and promote the clearance of intracellular Mtb through early superoxide anion production and autophagy induction, which is a novel role for neutrophil-derived EVs in the immune response to Mtb.

Keywords: Extracellular vesicles (EVs), Neutrophils, Tuberculosis, Macrophages, Autophagy

Received: 03 Nov 2017; Accepted: 30 Jan 2018.

Edited by:

Christopher Gregory, University of Edinburgh, United Kingdom

Reviewed by:

Bruce M. Hall, University of New South Wales, Australia
Maria Cecilia G. Marcondes, San Diego Biomedical Research Institute, United States  

Copyright: © 2018 Alvarez-Jimenez, Leyva-Paredes, García-Martínez, Vásquez-Flores, García-Paredes, Campillo-Navarro, Romo-Cruz, Rosales-Hernández, Castañeda-Casimiro, González-Pozos, Hernández, Wong Baeza, García-Pérez, Ortiz-Navarrete, Estrada-Parra, Serafin-López, Wong-Baeza, CHACON-SALINAS and Estrada-Garcia. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
PhD. ROMMEL CHACON-SALINAS, Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico, Mexico, rommelchacons@yahoo.com.mx
PhD. Iris Estrada-Garcia, Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico, Mexico, iestrada5@hotmail.com