The phylogenetic conseveration of the autophagy pathway attests to its fundamental importance to eukaryotic life and, in its role in xenophagy, it may represent one of the most evolutionarily ancient forms of host defense. It is not surprising to find that, later in evolution, with the emergence of multifacted immune responses to pathogens, there also emerged complex interrelationships between the autophagy pathway and other innate immune pathways. To date, all cellular sensors and pathways that are implicated in triggering pathogen-induced autophagy have had previously characterized roles in innate immune pathways. Recent advances discussed in this review indicate that, in addition to these previously characterized roles in innate immunity, a crucial conserved biological function of pattern recognition molecules, damage sensors, and cellular stress signaling pathways may be the activation of autophagy during infection with intracellular pathogens.
There is also increasing evidence that cells use a conserved set of molecular machinery to target unwanted “self-constituents” that they use to target unwanted “microbial invaders”. This machinery of selective autophagy centers largely upon ubiquitination, a signal already known to be important in regulate innate immune responses, as well as adaptor proteins such as p62 and NDP52 that bridge ubiquitin-tagged substrates to the autophagosomal protein, LC3. However, as further research on targeting unfolds, it seems likely that distinct forms of selective autophagy will be found to exist for different classes of pathogens. Moreover, the autophagic targeting of different classes of pathogens may have different biological outcomes, perhaps in cell type-specific fashions, with respect to pathogen degradation, regulation of innate and adaptive immune responses, and the consequences of such targeting for cell and organismal survival.
Finally, there is growing evidence that autophagy is involved in “tuning” the innate immune response and that such “tuning” may exert either positive or negative regulatory effects depending on the cell-type and stimulus. This paradigm may be operative in the pathogenesis of Crohn’s disease, as recent studies suggest that a central pathology may be a lack of autophagy protein-mediated downregulation of pro-inflammatory cytokine production in response to environmental innate immune stimuli. An interesting general emerging theme is that autophagy proteins may exert negative regulatory control on inflammatory signaling through autophagy-independent mechanisms. Thus, the conserved autophagy machinery may have dually evolved to both target pathogens for lysosome degradation through classical autophagy, as well as to prevent, through mechanisms not yet fully understood, detrimental inflammatory responses triggered by such pathogens.
In summary, great strides have been made in the past few years in our understanding of autophagy and innate immunity. Recent discoveries offer tantalizing clues as to how the autophagy pathway and other innate immune pathways are integrated to produce a concerted host defense. Yet, we are only beginning to appreciate the sophistication and complexity of such integration. A more precise understanding of cross-talk between autophagy and other aspects of innate immunity will be required before we can develop specific therapies that trigger, target or tune the innate immune response to combat pathogens and control auto-inflammatory diseases.