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Keywords:

  • innate immunity;
  • phagosome maturation;
  • cytokines;
  • inflammasome;
  • Irgm1

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Modulation of Autophagy by Cytokines
  5. Toll-Like Receptors and Autophagy
  6. ATP-Induced Autophagy and the Inflammasome
  7. Autophagy and Ubiquitin
  8. Autophagy and Antigen Presentation
  9. Concluding Remarks
  10. Acknowledgements
  11. References

Autophagy is a homeostatic mechanism for the catabolism of cytosolic constituents, including organelles, in times of stress and nutrient deprivation. In addition, autophagy has been linked to innate and adaptive immune responses to numerous infectious microorganisms, including mycobacteria. This review explores the role of autophagy in the responses of antigen-presenting cells to mycobacteria, including links with phagosome maturation, inflammasome activation and antigen presentation. In addition, the modulation of autophagy by cytokines and pathogen-derived stimuli is discussed.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Modulation of Autophagy by Cytokines
  5. Toll-Like Receptors and Autophagy
  6. ATP-Induced Autophagy and the Inflammasome
  7. Autophagy and Ubiquitin
  8. Autophagy and Antigen Presentation
  9. Concluding Remarks
  10. Acknowledgements
  11. References

Autophagy is an evolutionary conserved process for the targeting of cellular constituents, including damaged or surplus organelles, such as mitochondria and peroxisomes, to lysosomes and promotes cell survival by degrading long-lived cytosolic macromolecules during periods of amino-acid deprivation (Kuma et al., 2004; Shintani and Klionsky, 2004). Three distinct types of autophagy have been described; microautophagy, in which small volumes of cytosol are directly engulfed by lysosomes (Ahlberg et al., 1982); chaperone-mediated autophagy, in which specific proteins are recognized by a cytosolic chaperone and targeted to the lysosome (Dice, 1990). The third form, macroautophagy (hereafter referred to as autophagy, Fig. 1) involves the expansion of an isolation membrane, or phagophore, around a portion of the cell to form an autophagosome with a distinctive double-membrane, which can then fuse with lysosomes (Shintani and Klionsky, 2004).

image

Figure 1.  Autophagosome formation. Macroautophagy follows a series of steps regulated by autophagy-related (Atg) proteins. The first step involves the formation of an isolation membrane, or phagophore (initiation), which envelopes the target until it fuses with itself to form an autophagosome with a double membrane (elongation). The autophagosome can fuse with late endosomes and multivesicular bodies (MVB) to form an amphisome, which fuses with lysosomes to become an autolysosome (maturation). The initiation stages depend on a complex of the type III PI3 Kinase, hVPS34 with beclin 1 (Atg6) and the formation of phosphoinositol-3-phosphate (PI3P). Elongation is dependent on the Atg12 conjugation system, in which Atg12 forms a stable complex with Atg5 and Atg 16. This in turn triggers oligomerization on the outer membrane of the autophagosome and lipidation of light chain 3 (LC3) from the cytosloic form (LC3 I) to the membrane form (LC3 II). The Atg5-Atg12-Atg16 complex and LC3 II are recycled while LC3 II on the luminal membrane remains and is degraded in the autolysosome. After (Levine and Deretic, 2007) and (Nedelsky et al., 2008).

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Autophagy also contributes to innate and adaptive immune responses. It is involved in innate responses against numerous intracellular pathogens and may play an important role in the presentation of endogenous antigens (Levine and Deretic, 2007). Here, we discuss the potential role of autophagy in innate and adaptive immune responses to mycobacteria.

Modulation of Autophagy by Cytokines

  1. Top of page
  2. Summary
  3. Introduction
  4. Modulation of Autophagy by Cytokines
  5. Toll-Like Receptors and Autophagy
  6. ATP-Induced Autophagy and the Inflammasome
  7. Autophagy and Ubiquitin
  8. Autophagy and Antigen Presentation
  9. Concluding Remarks
  10. Acknowledgements
  11. References

Immunity to tuberculosis is reliant on a predominantly Th1-mediated response, characterized by the localized secretion of interferon-γ (IFN-γ), interleukin-12 (IL-12) and tumour necrosis factor-α (TNF-α) (reviewed by Hope and Vordermeier, 2005; Salgame, 2005). Conversely, Th2 responses in the lungs and periphery of patients have been associated with more severe disease (van Crevel et al., 2000; Mazzarella et al., 2003). Numerous studies have demonstrated that activation of macrophages and dendritic cells with IFN-γ increases intracellular killing of mycobacteria via NOS2-dependent and -independent mechanisms (see Hope et al., 2004; Purdy and Russell, 2007; Liu and Modlin, 2008 for reviews). One effector in the NOS2-independent response is the GTPase, Irgm1 (formerly LRG-47), which has specific anti-mycobacterial activity and is involved in phagosome biogenesis (MacMicking et al., 2003).

Mycobacteria have evolved mechanisms to inhibit phagosome maturation, preventing fusion with lysosomes, acidification and exposure of bacteria to lysosomal hydrolases (Russell, 2001; Deretic et al., 2006). When treated with IFN-γ, macrophages are able to overcome this block on phagosome maturation (Schaible et al., 1998; Via et al., 1998). Activation of macrophages with IFN-γ also induces autophagy and recruitment of the autophagosome marker microtubule-associated protein 1 light chain 3 (LC3) to the mycobacterial phagosome, along with Irgm1 (MacMicking et al., 2003; Gutierrez et al., 2004). Transfection of murine macrophages with Irgm1, or human macrophages with the human orthologue, IRGM, induces autophagosome formation, while transfection of cells with siRNA against Irgm1 inhibits IFN-γ-induced autophagosome formation (Gutierrez et al., 2004; Singh et al., 2006). Moreover, transfection of macrophages with siRNA against Beclin 1 or Atg7, both essential for autophagosome formation, abrogates the effects of IFN-γ on maturation of mycobacteria-containing phagosomes (Singh et al., 2006; Harris et al., 2007).

The effects of IFN-γ on phagosome maturation in macrophages may also be dependent on autocrine secretion of TNF-α. Tumour necrosis factor-α is essential for the formation and maintenance of the tubercular granuloma (Flynn and Chan, 2001) and is secreted by macrophages in response to infection with M. bovis Bacille Calmette-Guérin (BCG) and M. tuberculosis. This response is greatly enhanced following activation of the cells with IFN-γ (Harris et al., 2008). Treatment of human macrophages with TNF-α induces maturation of mycobacteria-containing phagosomes, while treatment of infected macrophages with the TNF-α blockers adalimumab, infliximab and etanercept inhibits IFN-γ-induced phagsome maturation (Harris et al., 2008). A number of studies suggest that TNF-α may be important in the modulation of autophagy. Ligation of CD40, coupled with exogenous or autocrine TNF-α signalling induces autophagy-dependent elimination of Toxoplasma gondii in infected macrophages (Andrade et al., 2006; Ling et al., 2006). In MCF-7 human breast cancer cells, TNF-α-induced autophagy is dependent on ERK1/2 signalling (Sivaprasad and Basu, 2008), while in Ewing sarcoma cells, TNF-α-induced autophagy is inhibited by activation of NF-κB and dependent on the production of reactive oxygen species (Djavaheri-Mergny et al., 2006). Activation of human atherosclerotic vascular smooth muscle cells with TNF-α up-regulates expression of the autophagy genes Beclin 1 and MAPLC3, an effect dependent on activation of the Jun Kinase pathway (Jia et al., 2006). Moreover, in T lymphoblastic leukaemic cell lines, autophagosome formation has been observed at an early stage of TNF-α-induced cell death (Jia et al., 1997). However, the effect of TNF-α on autophagy in macrophages infected with mycobacteria has yet to be determined.

While IFN-γ and TNF-α induce autophagy, the Th2 cytokines IL-4 and IL-13 have the opposite effect. Through activation of the Akt pathway, IL-13 inhibits starvation-induced autophagy in HT-29 human epithelial cells (Petiot et al., 2000; Arico et al., 2001). Both IL-4 and IL-13 signal through the IL-4Rα receptor, which forms a heterodimer with the gamma common (γc) chain or IL-13Rα1, and activates the Akt and STAT6 pathways. In human and murine macrophages both IL-4 and IL-13 inhibit starvation- and IFN-γ-induced autophagosome formation and autophagy-dependent maturation of mycobacteria-containing phagosomes (Harris et al., 2007). This inhibition is dependent on both signalling pathways; inhibition of starvation-induced autophagy on the Akt pathway, inhibition of IFN-γ-induced autophagy on the STAT6 pathway (Harris et al., 2007).

Toll-Like Receptors and Autophagy

  1. Top of page
  2. Summary
  3. Introduction
  4. Modulation of Autophagy by Cytokines
  5. Toll-Like Receptors and Autophagy
  6. ATP-Induced Autophagy and the Inflammasome
  7. Autophagy and Ubiquitin
  8. Autophagy and Antigen Presentation
  9. Concluding Remarks
  10. Acknowledgements
  11. References

The role of Toll-like receptors (TLR) in innate and adaptive immunity to M. tuberculosis is still somewhat controversial. Mycobacterial lipoproteins and CpG-containing DNA have been shown to bind TLR2 (dimerized with either TLR1 or TLR6) and TLR9, respectively, while TLR signalling through MyD88 and TIR-domain-containing adaptor protein inducing IFNβ (TRIF) results in proinflammatory, anti-mycobacterial responses (Korbel et al., 2008). Moreover, engagement of TLRs has also been shown to induce autophagy in macrophages. A recent study demonstrated that treatment of macrophages with LPS induces autophagy and enhances anti-mycobacterial responses (Xu et al., 2007). This effect was shown to be MyD88-independent and TRIF-dependent, although another study has shown TLR4-induced autophagy to be both MyD88- and TRIF-dependent (Shi and Kehrl, 2008). Moreover, activation of MyD88 or TRIF results in the recruitment of beclin 1 to the TLR4-signalling complex (Shi and Kehrl, 2008). This could suggest that engagement of TLR2/4 during engulfment leads to recruitment of autophagy proteins directly to the phagocytic cup. Sanjuan et al. (2007) observed that particles that engage TLRs during phagocytosis rapidly recruit Beclin 1 and LC3 to the developing phagosome. These phagosomes did not display double membranes but rapidly fused with lysosomes and acidified, possibly highlighting a novel pathway linking autophagy and phagosome maturation (Sanjuan et al., 2007). In this context, it is interesting that LC3 was found on latex bead-containing phagosomes in macrophages (Shui et al., 2008). Moreover, levels of LC3 on the phagosome increase following induction of autophagy by nutrient starvation. These data suggest a close link between phagosome biogenesis and autophagy (Shui et al., 2008). In addition, TLR7, which recognizes single-stranded RNA (ssRNA), has also been shown to induce autophagy in macrophages in a MyD88-dependent manner (Delgado et al., 2008). Although TLR7 is not directly involved in the response to mycobacteria, treatment of BCG-infected macrophages with imiquimod or ssRNA increases intracellular killing of mycobacteria, perhaps highlighting potential therapeutic applications (Delgado et al., 2008).

ATP-Induced Autophagy and the Inflammasome

  1. Top of page
  2. Summary
  3. Introduction
  4. Modulation of Autophagy by Cytokines
  5. Toll-Like Receptors and Autophagy
  6. ATP-Induced Autophagy and the Inflammasome
  7. Autophagy and Ubiquitin
  8. Autophagy and Antigen Presentation
  9. Concluding Remarks
  10. Acknowledgements
  11. References

Studies have demonstrated that treatment of infected human macrophages with adenosine 5′-triphosphate (ATP) enhances intracellular killing of mycobacteria (Lammas et al., 1997; Fairbairn et al., 2001; Stober et al., 2001; Biswas et al., 2008). These anti-microbial responses appear to be dependent on both apoptosis and autophagy. Apoptosis of infected macrophages has been shown to reduce intracellular viability of M. tuberculosis (Molloy et al., 1994; Fratazzi et al., 1999). Moreover, mycobacteria contained within apoptotic vesicles can be taken up by dendritic cells, which can in turn present mycobacterial antigens to CD8+ T cells following presentation via CD1 and major histocompatibility complex (MHC) Class 1 molecules (Schaible et al., 2003; Winau et al., 2006). Exposure to extracellular ATP induces apoptosis of human and bovine macrophages and increases intracellular killing of mycobacteria, an effect mediated through purinergic P2X7 receptors and an increase in cytosolic Ca2+ (Lammas et al., 1997; Smith et al., 2001; Placido et al., 2006). Similarly, acidification of mycobacteria-containing phagosomes and fusion with lysosomes is increased in macrophages treated with ATP and this effect is also P2X7-dependent (Fairbairn et al., 2001; Stober et al., 2001). A recent study has demonstrated that this increase in phagosome acidification and fusion with lysosomes is at least partially dependent on the induction of autophagy (Biswas et al., 2008). Adenosine 5′-triphosphate induces rapid autophagosome formation in macrophages and ATP-dependent phagosome–lysosome fusion and intracellular killing of BCG is inhibited by wortmannin, as well as by an anti-P2X7 antibody or the selective P2X7 antagonist, oxidized ATP (Biswas et al., 2008).

Interestingly, ATP is also a potent inducer of inflammasome activation and IL-1β secretion in LPS-stimulated macrophages (Cruz et al., 2007; Franchi et al., 2007). Assembly and activation of inflammasomes are essential processes in the innate immune response to pathogenic bacteria (Sutterwala et al., 2007). Inflammasomes are typically formed by at least one member of the cytosolic innate immune sensor family, the NOD-like receptors (NLR). The NLR family members NALP3, NAIP5 or Ipaf and the adaptor ASC are involved in caspase-1 activation in response to bacterial infection, triggering the processing and secretion of IL-1β and IL-18. Studies have shown that mycobacteria induce activation of the NALP3 inflammasome and subsequent secretion of IL-1β and IL-18 by macrophages, the latter via a mechanism dependent on the ESX-1 secretion system and lysosome exocytosis (Giacomini et al., 2001; Montero et al., 2004; Koo et al., 2008). However, mycobacteria may have also developed mechanisms for inhibiting inflammasome activation. A recent study has demonstrated that zmp1, a gene encoding a putative Zn2+ metalloproteinase in M. tuberculosis, is essential for inhibition of IL-1β processing in infected macrophages (Master et al., 2008). Infection of murine macrophages with zmp1−/−M. tuberculosis leads to inflammasome activation and increased secretion of IL-1β, along with enhanced maturation of mycobacteria-containing phagosomes and increased killing of intracellular mycobacteria by macrophages (Master et al., 2008). In addition, mice challenged by aerosol infection with zmp1−/−M. tuberculosis display a lower bacterial burden in the lungs compared with those infected with the wild-type bacteria (Master et al., 2008). In macrophages infected with Shigella flexneri, IPAF inhibits autophagy through caspase 1 activation, although genetic deletion of ASC has no effect (Suzuki et al., 2007). Disruption of autophagosome function, either by deletion of Atg16L, with 3MA or by siRNA knockdown of Atg7, enhances LPS-induced production of IL-1β and IL-18 in macrophages (Saitoh et al., 2008). Moreover, Atg16L1 deficiency causes TRIF-dependent activation of caspase 1 in response to LPS, suggesting that autophagy negatively regulates inflammasome activation and subsequent release of IL-1β and IL-18 (Saitoh et al., 2008). The mechanism behind these observations has yet to be elucidated. One possibility is that autophagosomes engulf and degrade inflammasome constituents in the cytosol and/or exocytic lysosomes.

Autophagy and Ubiquitin

  1. Top of page
  2. Summary
  3. Introduction
  4. Modulation of Autophagy by Cytokines
  5. Toll-Like Receptors and Autophagy
  6. ATP-Induced Autophagy and the Inflammasome
  7. Autophagy and Ubiquitin
  8. Autophagy and Antigen Presentation
  9. Concluding Remarks
  10. Acknowledgements
  11. References

A recent study has highlighted a novel non-oxidative mechanism by which macrophages can kill intracellular mycobacteria following their delivery to the lysosome (Alonso et al., 2007). Solubilized lysosomes from murine bone marrow-derived macrophages were found to have potent anti-bacterial properties that were associated with ubiquitin and ubiquitin-derived peptides (Alonso et al., 2007). Moreover, induction of autophagy increases the transfer of cytosolic proteins, including ubiquitinated peptides, to the lysosomes (Schaible et al., 1999; Alonso et al., 2007). In Drosophila melanogastor, autophagy has been shown to act as a compensatory degradation system when the ubiquitin-proteosome system is compromised (Pandey et al., 2007). This was dependent on histone deacetylase 6, which interacts with polyubiquinated proteins (Pandey et al., 2007). These studies highlight one mechanism through which autophagy may enhance anti-microbial responses against mycobacteria and other bacterial pathogens in macrophages, as well as linking autophagy with the ubiquitin-proteasome system.

Autophagy and Antigen Presentation

  1. Top of page
  2. Summary
  3. Introduction
  4. Modulation of Autophagy by Cytokines
  5. Toll-Like Receptors and Autophagy
  6. ATP-Induced Autophagy and the Inflammasome
  7. Autophagy and Ubiquitin
  8. Autophagy and Antigen Presentation
  9. Concluding Remarks
  10. Acknowledgements
  11. References

Autophagy has been implicated in the delivery of antigen to the endolysosomal degradation pathway, loading of MHC class II molecules with endogenous peptides and the generation of self-tolerant T cells. Thus, the role of autophagy in antigen presentation is multi-faceted. Autophagosomes converge with endosomes and lysosomes and thus deliver antigens for loading in MHC class II compartments. Autophagy can also deliver endogenous antigens to the MHC II pathway (Schmid et al., 2007), enhancing presentation to CD4+ T cells (Brazil et al., 1997; Nimmerjahn et al., 2003; Dorfel et al., 2005; Paludan et al., 2005). These studies show a direct role for autophagy in the delivery of endogenous proteins to the MHC class II pathway and suggest that autophagy is a means by which the peptide repertoire presented by MHC class II molecules may be extended from exogenous to endogenous antigens. There is also evidence that autophagy-associated proteins, including LC3, gain access to MHC II compartments (Dengjel et al., 2005). Moreover, the induction (with rapamycin/starvation) or suppression (with 3-MA/RNAi knockdown) of autophagy has direct effects on MHC II-dependent peptide presentation (Munz, 2006; Vyas et al., 2008). A recent study has also suggested that, in the absence of autophagy, endogenous peptides might not be presented by MHC class II molecules, resulting in a failure to tolerize self-reactive T lymphocytes (Nedjic et al., 2008).

Autophagy may also be involved in the generation of MHC class I-restricted responses. Li et al. (2008) have demonstrated that autophagy plays an important role in antigen sequestration and delivery to dendritic cells for cross-presentation of tumour antigens (Li et al., 2008). This study also showed that isolated autophagosomes could be used as an antigen source for cross-presentation after being loaded into dendritic cells (DC). This approach may have potential in vaccine development, where cross-presentation of antigen to CD8+ T lymphocytes is required.

In immune responses to M. tuberculosis and M. bovis, the role of autophagy in antigen presentation has not been explored in detail. However, there is a large body of evidence highlighting the importance of Th1-biased immune responses and CD8+ T lymphocytes in immunity to mycobacteria. Coupled with autophagy-dependent phagosome maturation and intracellular killing of mycobacteria in macrophages, it seems likely that the induction of autophagy will also enhance antigen presentation via MHC class I and class II molecules. The induction of autophagy in bovine macrophages and monocyte-derived macrophages and DC via starvation and IFN-γ has recently been established and this affects intracellular survival of BCG within macrophages (J. Harris and J. C. Hope unpublished observation). The demonstration that autophagy can be induced in bovine, as well as human, antigen-presenting cells will facilitate the investigation of the role of this process in the immune response to mycobacteria both in vitro and in vivo.

Concluding Remarks

  1. Top of page
  2. Summary
  3. Introduction
  4. Modulation of Autophagy by Cytokines
  5. Toll-Like Receptors and Autophagy
  6. ATP-Induced Autophagy and the Inflammasome
  7. Autophagy and Ubiquitin
  8. Autophagy and Antigen Presentation
  9. Concluding Remarks
  10. Acknowledgements
  11. References

It has yet to be determined whether autophagy contributes to immune responses against mycobacteria in vivo, but the immunomodulatory potential of this process is clear. Through its effects on phagosome maturation, inflammasome activation and antigen presentation, autophagy could play a significant role in innate and adaptive immunity to mycobacteria and other infectious microorganisms. Moreover, autophagy may prove an attractive target for future therapeutics and vaccines against tuberculosis.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Modulation of Autophagy by Cytokines
  5. Toll-Like Receptors and Autophagy
  6. ATP-Induced Autophagy and the Inflammasome
  7. Autophagy and Ubiquitin
  8. Autophagy and Antigen Presentation
  9. Concluding Remarks
  10. Acknowledgements
  11. References
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