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The scavenger protein apoptosis inhibitor of macrophages (AIM) potentiates the antimicrobial response against Mycobacterium tuberculosis by enhancing autophagy.

ABSTRACT: Apoptosis inhibitor of macrophages (AIM), a scavenger protein secreted by tissue macrophages, is transcriptionally regulated by the nuclear receptor Liver X Receptor (LXR) and Retinoid X Receptor (RXR) heterodimer. Given that LXR exerts a protective immune response against M. tuberculosis, here we analyzed whether AIM is involved in this response. In an experimental murine model of tuberculosis, AIM serum levels peaked dramatically early after infection with M. tuberculosis, providing an in vivo biological link to the disease. We therefore studied the participation of AIM in macrophage response to M. tuberculosis in vitro. For this purpose, we used the H37Rv strain to infect THP-1 macrophages transfected to stably express AIM, thereby increasing infected macrophage survival. Furthermore, the expression of this protein enlarged foam cell formation by enhancing intracellular lipid content. Phagocytosis assays with FITC-labeled M. tuberculosis bacilli indicated that this protein was not involved in bacterial uptake; however, AIM expression decreased the number of intracellular cfus by up to 70% in bacterial killing assays, suggesting that AIM enhances macrophage mycobactericidal activity. Accordingly, M. tuberculosis-infected AIM-expressing cells upregulated the production of reactive oxygen species. Moreover, real-time PCR analysis showed increased mRNA levels of the antimicrobial peptides cathelicidin and defensin 4B. These increases were concomitant with greater cellular concentrations of the autophagy-related molecules Beclin 1 and LC3II, as well as enhanced acidification of mycobacterial phagosomes and LC3 co-localization. In summary, our data support the notion that AIM contributes to key macrophage responses to M. tuberculosis.

SUBMITTER: Sanjurjo L

PROVIDER: S-EPMC3817138 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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The scavenger protein apoptosis inhibitor of macrophages (AIM) potentiates the antimicrobial response against Mycobacterium tuberculosis by enhancing autophagy.

Sanjurjo Lucía L Amézaga Núria N Vilaplana Cristina C Cáceres Neus N Marzo Elena E Valeri Marta M Cardona Pere-Joan PJ Sarrias Maria-Rosa MR

PloS one 20131104 11

Apoptosis inhibitor of macrophages (AIM), a scavenger protein secreted by tissue macrophages, is transcriptionally regulated by the nuclear receptor Liver X Receptor (LXR) and Retinoid X Receptor (RXR) heterodimer. Given that LXR exerts a protective immune response against M. tuberculosis, here we analyzed whether AIM is involved in this response. In an experimental murine model of tuberculosis, AIM serum levels peaked dramatically early after infection with M. tuberculosis, providing an in vivo ...[more]

PMID: 24223991

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Project description:BAG2 (BCL2 associated athanogene 2) is associated with cell fate determination in response to various pathological conditions. However, the effects of BAG2 on M. tuberculosis-induced endoplasmic reticulum (ER) stress remain elusive. Herein, we report that M. tuberculosis infection of macrophages triggered ER stress and downregulated BAG2 expression. Overexpression of BAG2 enhanced autophagic flux and activated macroautophagy/autophagy targeted to the ER (reticulophagy). In addition, through increasingly localizing SQSTM1 to the ER in BAG2-overexpressing macrophages, we found that the autophagy receptor protein SQSTM1/p62 (sequestosome 1) is associated with the BAG2-induced reticulophagy. Our data also confirmed that BAG2 could render cells resistant to M. tuberculosis-induced cellular damage, and the anti-apoptotic effects of BAG2 in M. tuberculosis-treated macrophages were partially abolished by the autophagic flux inhibitor bafilomycin A1. Furthermore, the dissociation of BECN1 and BCL2 mediated by activation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) was responsible for BAG2-activated autophagy. In addition, XBP1 downstream of the ERN1/IRE1 signaling pathway was bound to the Bag2 promoter region and transcriptionally inhibited BAG2 expression. Collectively, these results indicated that BAG2 has anti-apoptotic effects on M. tuberculosis-induced ER stress, which is dependent on the promotion of autophagic flux and the induction of selective autophagy. We revealed a potential host defense mechanism that links BAG2 to ER stress and autophagy during M. tuberculosis infection.AbbreviationsATF6: activating transcription factor 6; BECN1: beclin 1; Baf A1: bafilomycin A1; CASP3: caspase 3; DDIT3/CHOP/GADD153: DNA damage inducible transcript 3; DAPI: 4',6-diamidino-2-phenylindole; EIF2AK3/PERK: eukaryotic translation initiation factor 2 alpha kinase 3; ER: endoplasmic reticulum; ERN1/IRE1: endoplasmic reticulum to nucleus signaling 1; HSPA5/GRP78/BiP: heat shock protein 5; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MAPK/ERK: mitogen-activated protein kinase; SQSTM1/p62: sequestosome 1; UPR: unfolded protein response; XBP1: x-box binding protein 1.

Dataset Information

The scavenger protein apoptosis inhibitor of macrophages (AIM) potentiates the antimicrobial response against Mycobacterium tuberculosis by enhancing autophagy.

Publications

The scavenger protein apoptosis inhibitor of macrophages (AIM) potentiates the antimicrobial response against Mycobacterium tuberculosis by enhancing autophagy.

Similar Datasets

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