title: Nucleotide-oligomerizing domain-1 (NOD1) receptor activation induces pro-inflammatory responses and autophagy in human alveolar macrophages.
abstract: BACKGROUND
  Nucleotide-binding oligomerizing domain-1 (NOD1) is a cytoplasmic receptor involved in recognizing bacterial peptidoglycan fragments that localize to the cytosol. NOD1 activation triggers inflammation, antimicrobial mechanisms and autophagy in both epithelial cells and murine macrophages. NOD1 mediates intracellular pathogen clearance in the lungs of mice; however, little is known about NOD1's role in human alveolar macrophages (AMs) or its involvement in Mycobacterium tuberculosis (Mtb) infection.
  
  
  METHODS
  AMs, monocytes (MNs), and monocyte-derived macrophages (MDMs) from healthy subjects were assayed for NOD1 expression. Cells were stimulated with the NOD1 ligand Tri-DAP and cytokine production and autophagy were assessed. Cells were infected with Mtb and treated with Tri-DAP post-infection. CFUs counting determined growth control, and autophagy protein recruitment to pathogen localization sites was analyzed by immunoelectron microscopy.
  
  
  RESULTS
  NOD1 was expressed in AMs, MDMs and to a lesser extent MNs. Tri-DAP stimulation induced NOD1 up-regulation and a significant production of IL1β, IL6, IL8, and TNFα in AMs and MDMs; however, the level of NOD1-dependent response in MNs was limited. Autophagy activity determined by expression of proteins Atg9, LC3, IRGM and p62 degradation was induced in a NOD1-dependent manner in AMs and MDMs but not in MNs. Infected AMs could be activated by stimulation with Tri-DAP to control the intracellular growth of Mtb. In addition, recruitment of NOD1 and the autophagy proteins IRGM and LC3 to the Mtb localization site was observed in infected AMs after treatment with Tri-DAP.
  
  
  CONCLUSIONS
  NOD1 is involved in AM and MDM innate responses, which include proinflammatory cytokines and autophagy, with potential implications in the killing of Mtb in humans.
authors.forename: Esmeralda
authors.initials: E
authors.lastname: Juárez
authors.forename: Claudia
authors.initials: C
authors.lastname: Carranza
authors.forename: Fernando
authors.initials: F
authors.lastname: Hernández-Sánchez
authors.forename: Elva
authors.initials: E
authors.lastname: Loyola
authors.forename: Dante
authors.initials: D
authors.lastname: Escobedo
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: León-Contreras
authors.forename: Rogelio
authors.initials: R
authors.lastname: Hernández-Pando
authors.forename: Martha
authors.initials: M
authors.lastname: Torres
authors.affiliation: Department of Microbiology, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, México City, México. eduardosadadiaz@yahoo.com.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Sada
mesh_terms: D001343:Autophagy / Q000187:drug effects; D002478:Cells, Cultured; D015169:Colony Count, Microbial; D016207:Cytokines / Q000378:metabolism*; D003960:Diaminopimelic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism* / Q000382:microbiology; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism* / Q000382:microbiology; D009169:Mycobacterium tuberculosis / Q000254:growth & development; D053474:Nod1 Signaling Adaptor Protein / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D014397:Tuberculosis, Pulmonary / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D016207:Cytokines; C555437:L-Ala-gamma-D-Glu-meso-diaminopimelic acid; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; C119067:NOD1 protein, human; D053474:Nod1 Signaling Adaptor Protein; D009842:Oligopeptides; D003960:Diaminopimelic Acid; D019204:GTP-Binding Proteins; C513539:IRGM protein, human