Autophagy and IL-1 Family Cytokines

Abstract

Autophagy is an important intracellular homeostatic mechanism for the targeting of cytosolic constituents, including organelles, for lysosomal degradation. Autophagy plays roles in numerous physiological processes, including immune cell responses to endogenous and exogenous pathogenic stimuli. Moreover, autophagy has a potentially pivotal role to play in the regulation of inflammatory responses. In particular, autophagy regulates endogenous inflammasome activators, as well as inflammasome components and pro-IL-1β. As a result, autophagy acts a key modulator of IL-1β and IL-18, as well as IL-1α, release. This review focuses specifically on the role autophagy plays in regulating the production, processing, and secretion of IL-1 and IL-18 and the consequences of this important function.

Keywords: IL-1; IL-18; autophagosome; autophagy; cytokines; inflammasome; inflammation; interleukin.

Figure 1

Pathways for the regulation of IL-1β by autophagy. Autophagy regulates IL-1β production, processing, and secretion through a number of mechanisms. In the absence of autophagy, stimulation of macrophages or dendritic cells with TLR3 or TLR4 ligands leads to a TRIF-dependent, mitochondrial ROS/DNA-dependent increase in the production, processing, and secretion of IL-1β, suggesting that autophagy normally limits the presence of these stimuli in the cytosol. These stimuli induce inflammasome assembly, but may also increase transcription of pro-IL-1β. Conversely, induction of autophagy in cells stimulated with TLR ligands leads to the sequestration and lysosomal degradation of pro-IL-1β, thus limiting the availability of the cytokine for subsequent processing and secretion. In addition, the inflammasome components ASC, NLRP3, and AIM2 can also be sequestered into autophagosomes. The effects of autophagy on transcription of pro-IL-1β are complex: autophagy down-regulates p62, which may be required for NF-κB activation, but also down-regulates IκB, promoting NF-κB nuclear translocation. Induction of autophagy in the presence of inflammasome-activating stimuli, such as ATP, nigericin and particulates, and crystals, can lead to increased secretion of IL-1β suggesting that autophagosomes may act as part of an exocytic pathway and possibly also a platform for inflammasome assembly, although it is not yet clear whether fully assembled inflammasomes are sequestered.