NOD2 enhances the innate response of alveolar macrophages to Mycobacterium tuberculosis in humans

Abstract

A role for the nucleotide-binding oligomerization domain 2 (NOD2) receptor in pulmonary innate immune responses has recently been explored. In the present study, we investigated the role that NOD2 plays in human alveolar macrophage innate responses and determined its involvement in the response to infection with virulent Mycobacterium tuberculosis. Our results showed that NOD2 was expressed in human alveolar macrophages, and significant amounts of IL-1β, IL-6, and TNF-α were produced upon ligand recognition with muramyldipeptide (MDP). NOD2 ligation induced the transcription and protein expression of the antimicrobial peptide LL37 and the autophagy enzyme IRGM in alveolar macrophages, demonstrating a novel function for this receptor in these cells. MDP treatment of alveolar macrophages improved the intracellular growth control of virulent M. tuberculosis; this was associated with a significant release of TNF-α and IL-6 and overexpression of bactericidal LL37. In addition, the autophagy proteins IRGM, LC3 and ATG16L1 were recruited to the bacteria-containing autophagosome after treatment with MDP. In conclusion, our results suggest that NOD2 can modulate the innate immune response of alveolar macrophages and play a role in the initial control of respiratory M. tuberculosis infections.Keywords: Alveolar macrophage r Autophagy r Innate immunity r NOD2 r Tuberculosis Supporting Information available online IntroductionThe recognition of pathogen-associated molecular patterns by innate immune receptors is essential for the initiation and coordination of the immune mechanisms responsible for host proCorrespondence: Dr. Eduardo Sada e-mail: eduardosadadiaz@yahoo.com tection against lung-invading pathogens [1]. The innate immune recognition is based on a limited repertoire of pattern recognition receptors, which sense conserved microbial components known as pathogen associated molecular patterns. The pattern recognition receptors include the members of the Toll-like receptor (TLR) family and the nucleotide-binding oligomerization domain (NOD) proteins (NOD-like receptors, NLRs), among others [2,3].The NLR proteins have been demonstrated to play an important role in the defense against respiratory agents, includingwww.eji-journal.eu Eur. J. Immunol. 2012. 42: 880-889 Immunity to Infection 881Pseudomonas aeruginosa, Streptococcus pneumoniae, Legionella pneumophila, and Mycobacterium tuberculosis [1,4,5]. The NOD proteins, members of the NLR family, are cytoplasmic receptors implicated in the recognition of bacterial molecules produced during the synthesis and/or degradation of peptidoglycan. Specifically, NOD2 senses the cytosolic presence of muramyldipeptide (MDP) [6,7]. Activation of NOD2 by bacterial products can stimulate two major signaling pathways to activate caspase-1 and pro-inflammatory responses, including the NF-κB pathway and the inflammasome pathway [5]. Upon ligand recognition, NOD2 activates the receptor-interacting protein-2 kinase (Rip2), which forms a multiprotein complex via its caspase activation...

The innate immune response in human tuberculosis

“…However, functional polymorphisms in both IRGM and the autophagy gene ATG16L1 did not have a major impact on Mtb‐induced cytokine production in healthy volunteers, although a moderate effect was observed on IFN‐γ production by the ATG16L1 T300A polymorphism (Kleinnijenhuis et al ., 2011). IRGM and other autophagic markers such as LC3 and ATG16L1 are recruited to Mtb‐containing compartments by the activation of the innate immune receptor NOD2 in Mtb‐infected human AMs (Juárez et al ., 2012). However, the precise mechanism by which this family of proteins control the cell autonomous response to Mtb is not known.…”

Autophagy in the Fight Against Tuberculosis

“…Non-TLR pathways have also been implicated in regulation of autophagy upon M. tuberculosis infection. One of the examples is the signaling cascade triggered by NOD-like receptor 2 (NOD2), which is an intracellular receptor that recognizes bacterial molecules (i.e., peptidoglycan) and induces expression of proteins that upregulate autophagy, such as IRGM, LC3, and ATG16L1, contributing to decreased M. tuberculosis virulence ( Juarez et al, 2012).…”

Common Polymorphisms in the CD43 Gene Region Are Associated with Tuberculosis Disease and Mortality

“…Most of this work has focused on macrophage receptors that initiate phagocytosis and mediate specific host immune responses. Numerous macrophage receptors that recognize MTB have been described, including Toll-like receptors (TLR1, -2, -4, -6, -8, and -9) (14), nucleotide binding oligomerization domain protein 2 (NOD2) (15), RIG-I-Like receptors (STING), C-type lectin receptors (DC-SIGN and CLEC4E/Mincle) (16,17), and CD43 (18)(19)(20). The details of how human genetic variation of receptors modulates mycobacterium TB (MTB) uptake and subsequent signaling events are largely unknown.…”