Autophagy in inflammatory diseases

Abstract

Autophagy provides a mechanism for the turnover of cellular organelles and proteins through a lysosome-dependent degradation pathway. During starvation, autophagy exerts a homeostatic function that promotes cell survival by recycling metabolic precursors. Additionally, autophagy can interact with other vital processes such as programmed cell death, inflammation, and adaptive immune mechanisms, and thereby potentially influence disease pathogenesis. Macrophages deficient in autophagic proteins display enhanced caspase-1-dependent proinflammatory cytokine production and the activation of the inflammasome. Autophagy provides a functional role in infectious diseases and sepsis by promoting intracellular bacterial clearance. Mutations in autophagy-related genes, leading to loss of autophagic function, have been implicated in the pathogenesis of Crohn's disease. Furthermore, autophagy-dependent mechanisms have been proposed in the pathogenesis of several pulmonary diseases that involve inflammation, including cystic fibrosis and pulmonary hypertension. Strategies aimed at modulating autophagy may lead to therapeutic interventions for diseases associated with inflammation.

Figure 1

The “macroautophagic” pathway responds to stimulation by various environmental cues including nutrient availability or noxious agents, which result in the accumulation of damaged proteins and/or organelles as well as pathogenic bacteria or viral infection. In the nucleation phase, a preautophagosomal structure develops from subcellular membranes and subsequently evolves into the phagophore or isolation membrane. The isolation membrane then expands to surround and engulf a cytoplasmic “cargo” of material targeted for degradation, culminating in double-membraned autophagosomes. Finally, the fusion of autophagosomes with lysosomes results in the formation of the autolysosome. During the degradative phase of autophagy, the encapsulated contents of autolysosomes are digested by lysosomal degradative enzymes (e.g., cathepsins and other acid hydrolases). The digested contents are then released to the cytosol for reutilization in anabolic pathways.

Figure 2

Autophagy as an adaptive cellular process potentially impacts the progression of inflammatory diseases by several possible mechanisms. (i) Autophagy, by acting as a “xenophagic” response, directly participates in bacterial clearance, through the encapsulation and lysosomal delivery of invading bacteria for degradation. (ii) Autophagic processes can assist in antigen presentation through the digestion of invading pathogens. (iii) Autophagic proteins play a role in the dampening proinflammatory responses, including proinflammatory cytokine secretion, through the maintenance of mitochondrial quality. (iv) Autophagic degradation of denatured protein aggregates may play a protective role in tissues such that impaired function has been associated with diseases such as cystic fibrosis [5]. (v) Autophagic protein LC3B potentially regulates other cellular processes as recently described in a model of hypoxia-induced pulmonary hypertension. In these studies, LC3B was found to inhibit vascular cell proliferation and promote smooth muscle cell apoptosis, collectively associated with protection in this model [29].