Modulation of inflammation by autophagy: Consequences for human disease

Abstract

Autophagy and inflammation are 2 fundamental biological processes involved in both physiological and pathological conditions. Through its crucial role in maintaining cellular homeostasis, autophagy is involved in modulation of cell metabolism, cell survival, and host defense. Defective autophagy is associated with pathological conditions such as cancer, autoimmune disease, neurodegenerative disease, and senescence. Inflammation represents a crucial line of defense against microorganisms and other pathogens, and there is increasing evidence that autophagy has important effects on the induction and modulation of the inflammatory reaction; understanding the balance between these 2 processes may point to important possibilities for therapeutic targeting. This review focuses on the crosstalk between autophagy and inflammation as an emerging field with major implications for understanding the host defense on the one hand, and for the pathogenesis and treatment of immune-mediated diseases on the other hand.

Keywords: autoimmune diseases; autoinflammatory diseases; autophagy; carcinogenesis; infectious diseases; inflammation.

Figure 1.

The process of autophagy in eukaryotic cells and its involvement in cellular homeostasis, metabolism, and the immune system. Autophagy is induced both by metabolic and immune signals comprising pathogen recognition and stimulation by proinflammatory cytokines. Upon autophagy triggering through any of these pathways, the MAP1LC3B (depicted as unconjugated LC3B-I and PE-conjugated LC3B-II) and ATG12 conjugation systems, as well as BECN1 and class III PtdIns3K, are activated that are critical for autophagosome formation. After engulfment of the autophagic cargo, autophagosomes proceed to lysosomal fusion, leading to degradation of the sequestered content. In case the autophagic cargo originates from intracellular organelles or protein complexes, the degraded fragments are utilized for metabolic purposes to generate ATP and provide the cell with free amino acids. In contrast, autophagy-mediated degradation of extracellular material, especially microbes, enables pathogen killing and activation of adaptive immunity by MHC-dependent antigen presentation.

Figure 2.

The interplay between autophagy and IL1B-inflammasome activation. Production of the pro-inflammatory cytokines IL1B and IL18 is pivotal in antimicrobial host defense, since this leads to activation of both innate and adaptive immune responses including Th1 and Th17. Autophagy potently regulates these immune responses by several means. First, autophagy inhibits IL1B and IL18 production through digestion of dysfunctional mitochondria and thereby prevention of mitochondrial ROS release that is known to activate the inflammasome. Second, autophagy is capable of targeting inflammasome complexes for degradation, which prevents cleavage of pro-IL1B and pro-IL18 into their biologically active counterparts. Finally, the autophagy machinery engulfs and eradicates pro-IL1B proteins, representing another level of IL1B regulation. DAMP, danger-associated molecular pattern; PAMP, pathogen-associated molecular pattern; PRR, pattern recognition receptor; ROS, reactive oxygen species.

Figure 3.

Interplay between autophagy and inflammation in the pathogenesis of Crohn disease. Multiple facets of inflammatory pathways involved in CD pathogenesis are influenced by autophagy, ranging on the one hand from defective microbial recognition and phagocytosis in dendritic cells (DCs) through the PRR NOD2, diminished antigen processing and presentation on MHC class I/II caused by genetic variants in ATG16L1, IRGM, and CALCOCO2, and on the other hand to a loss of inhibition of IL1B and IL18 production, important pro-inflammatory mediators leading to generation of Th1 and Th17 responses. Furthermore, genetic variation in ATG16L1 impairs the capacity of Paneth cells to excrete antimicrobial peptides, including DEFA/α- and DEFB/β-defensins. All together, these defects allow for microbial overgrowth and lead to hyperinflammation. DC, dendritic cell; TCR, T cell receptor.

Figure 4.

The role of crosstalk between autophagy and inflammation in cancer. Induction of autophagy is a double-edged sword with both protumorigenic and antitumorigenic effects. Processes downstream of autophagy that influence tumor progression and treatment resistance are comprised of cell survival pathways and recruitment of innate immune cells following release of DAMPs by necrotic tumor cells. Conversely, antitumorigenic signaling is evoked by autophagy-mediated immunogenic cell death and inhibition of tumor-associated inflammation. An outstanding example of the diverse and apparently opposite effects of autophagy on cancer initiation and progression is the induction of cellular senescence and subsequent removal of senescent cells; depending on the cellular context this is either pro- or anti-tumorigenic. APC, antigen-presenting cell.