MIF and autophagy: a novel link beyond “eating”

Bounkari, Omar El; Bernhagen, Jürrgen

doi:10.1038/cr.2012.76

Cited by 10 publications

(10 citation statements)

References 16 publications

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“…Furthermore, Mif , a proinflammatory cytokine, was an upregulated component of LISA (Fig. 7e ) [ 46 ]. Overexpression of MIF was also confirmed by western blot analysis at the protein level (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The exact role of MIF in autophagy regulation is not fully understood. Both autophagy promoting and autophagy inhibiting properties have been reported for MIF [ 46 , 75 ]. However, MIF-overexpressing macrophages might be potentially involved in the enhancement of Leishmania infection in vivo by recruiting new uninfected host macrophages to the infection.…”

Section: Discussionmentioning

confidence: 99%

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Autophagic digestion of Leishmania major by host macrophages is associated with differential expression of BNIP3, CTSE, and the miRNAs miR-101c, miR-129, and miR-210

Frank¹,

Marcu²,

Petersen

et al. 2015

Parasites Vectors

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BackgroundAutophagy participates in innate immunity by eliminating intracellular pathogens. Consequently, numerous microorganisms have developed strategies to impair the autophagic machinery in phagocytes. In the current study, interactions between Leishmania major (L. m.) and the autophagic machinery of bone marrow-derived macrophages (BMDM) were analyzed.MethodsBMDM were generated from BALB/c mice, and the cells were infected with L. m. promastigotes. Transmission electron microscopy (TEM) and electron tomography were used to investigate the ultrastructure of BMDM and the intracellular parasites. Affymetrix® chip analyses were conducted to identify autophagy-related messenger RNAs (mRNAs) and microRNAs (miRNAs). The protein expression levels of autophagy related 5 (ATG5), BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3), cathepsin E (CTSE), mechanistic target of rapamycin (MTOR), microtubule-associated proteins 1A/1B light chain 3B (LC3B), and ubiquitin (UB) were investigated through western blot analyses. BMDM were transfected with specific small interfering RNAs (siRNAs) against autophagy-related genes and with mimics or inhibitors of autophagy-associated miRNAs. The infection rates of BMDM were determined by light microscopy after a parasite-specific staining.ResultsThe experiments demonstrated autophagy induction in BMDM after in vitro infection with L. m.. The results suggested a putative MTOR phosphorylation-dependent counteracting mechanism in the early infection phase and indicated that intracellular amastigotes were cleared by autophagy in BMDM in the late infection phase. Transcriptomic analyses and specific downregulation of protein expression with siRNAs suggested there is an association between the infection-specific over expression of BNIP3, as well as CTSE, and the autophagic activity of BMDM. Transfection with mimics of mmu-miR-101c and mmu-miR-129-5p, as well as with an inhibitor of mmu-miR-210-5p, demonstrated direct effects of the respective miRNAs on parasite clearance in L. m.-infected BMDM. Furthermore, Affymetrix® chip analyses revealed a complex autophagy-related RNA network consisting of differentially expressed mRNAs and miRNAs in BMDM, which indicates high glycolytic and inflammatory activity in the host macrophages.ConclusionsAutophagy in L. m.-infected host macrophages is a highly regulated cellular process at both the RNA level and the protein level. Autophagy has the potential to clear parasites from the host. The results obtained from experiments with murine host macrophages could be translated in the future to develop innovative and therapeutic antileishmanial strategies for human patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s13071-015-0974-3) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Autophagic digestion of Leishmania major by host macrophages is associated with differential expression of BNIP3, CTSE, and the miRNAs miR-101c, miR-129, and miR-210

Frank¹,

Marcu²,

Petersen

et al. 2015

Parasites Vectors

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“…Given the suggested links among JAB1, Bcl-Gs, MIF, and autophagy (Chuang et al, 2012; Bounkari and Bernhagen, 2012; Wu et al, 2012), the members of the Bcl-2 pathway and JAB1’s possible role in autophagy will be closely examined in future experiments.…”

Section: Discussionmentioning

confidence: 99%

Deletion of macrophage migration inhibitory factor worsens stroke outcome in female mice

Turtzo

Persky

et al. 2013

Neurobiology of Disease

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Sex is an important factor in the response to ischemic insults in both the laboratory and the clinic. Inflammation and cell death are points where sex-specific pathways diverge in stroke, and serum estrogen levels status affect the response to inflammation. The cytokine macrophage migration inhibitory factor (MIF) is detrimental in experimental stroke models in male animals. However MIF is known to have sex-specific actions on inflammation and wound healing. The role of MIF in the ischemic female brain has not been evaluated. A transient middle cerebral artery occlusion (MCAO/90 minutes) model was used to induce stroke in male, intact female, and ovariectomized female wildtype (WT) and MIF knockout (KO) mice. Infarct size was quantified 72 hours after stroke. Protein and cytokine levels were assessed post stroke. Female MIF KO mice had significantly larger strokes compared to WT females (mean hemispheric infarct±SEM: 63%±2% versus 29%±3%; n=8; p<0.05). Ovariectomized female MIF KO mice also had larger infarcts than ovariectomized WT littermates (70%±3% versus 47%±4%; n=11; p<0.05). In males, however, infarct size was equivalent between MIF KO and WT mice (63%±2% versus 67%±3%; n=9; p=0.25). There were no significant differences in cytokine levels at 6 hours post-infarct between mice of either genotype in brain. MIF KO females displayed more microglial activation (ionized calcium binding adaptor molecule 1 (Iba1) immunofluoresence) after stroke than did WT mice or MIF KO males. The larger infarcts in MIF KO females were associated with an early increase in mitochondrial localization of Jun activation domain-binding protein 1 (JAB1). Loss of MIF exacerbated injury in the female brain after experimental stroke, which was independent of changes in pro-inflammatory cytokine levels. This response is sex-specific, and is in part independent of physiological serum levels of estrogen.

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“…With the caveat that this study was performed in mice of mixed genetic backgrounds, it highlights the complex nature and important interaction between MIF and aging biology. Recent in vitro studies have also highlighted MIF's role in the modulation of glucose and fat metabolism, mitochondrial respiration, stem cell survival, ubiquitin-proteosome signaling, redox balance, cell cycle regulation, autophagy, and cellular senescence (13,40,46,105,115,142,156).…”

Section: Mif and Longevitymentioning

confidence: 99%