Immune Netw.  2013 Feb;13(1):1-9. 10.4110/in.2013.13.1.1.

Autophagy as an Innate Immune Modulator

• Oh JE
• Lee HK

• KMID: 2150764
• DOI: http://doi.org/10.4110/in.2013.13.1.1

Abstract

Autophagy is a fundamental cellular process in eukaryotic cells for maintaining homeostasis by degrading cellular proteins and organelles. Recently, the roles of autophagy have been expanded to immune systems, which in turn modulate innate immune responses. More specifically, autophagy acts as a direct effector for protection against pathogens, as well as a modulator of pathogen recognition and downstream signaling in innate immune responses. In addition, autophagy controls autoimmunity and inflammatory disorders by negative regulation of immune signaling. In this review, we focus on recent advances in the role of autophagy in innate immune systems.

Keyword

Autophagy; Toll-like receptors; RIG-I-like receptors; NOD-like receptors

MeSH Terms

Autoimmunity
Autophagy
Eukaryotic Cells
Homeostasis
Immune System
Immunity, Innate
Organelles
Proteins
Toll-Like Receptors
Proteins
Toll-Like Receptors

Figure

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  Figure 1 Pathogen elimination by autophagy. Intracellular pathogens that are either free in the cytosol or inside phagosomes are engulfed by autophagosomes and degraded inside autolysosomes. In the case of Mycobacterium tuberculosis, which blocks phagolysosomal fusion for survival, mycobacterial extracellular DNA, which is exposed to host cytosol by phagosomal permeabilization via ESX-1 secretion system, is recognized by the STING-dependent cytosolic pathway. The ubiquitinated bacterial DNA, which binds to the autophagosome-associated protein LC3 via adaptor protein p62 or NDP52, is delivered to the autophagosome.

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  Figure 2 Autophagy induction by TLR activation. (A) TLR4 activation by LPS, and TLR7 activation by two different ligands (ssRNA and imiquimod) elicits autophagosome formation, which enables the degradation of mycobacteria. (B) Upon phagocytosis of zymosan, LC3 is rapidly recruited to the phagosomal membrane, which promotes the maturation of the phagosome to fuse with the lysosome. Notably, LC3 recruitment to the phagosomal membrane is not associated with autophagosome formation.

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  Figure 3 NLR-mediated autophagy induction. Detection of γ-D-glutamyl-meso-diaminopimelic acid (iE-DAP) and MDP by NOD1 and NOD2, respectively, induces the autophagosome formation, which leads to the bacterial clearance and MHC class II-associated antigen presentation.

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  Figure 4 Role of autophagy in antiviral immune response. In pDCs, autophagy facilitates the viral sensing by delivering the viral replication intermediates in the cytosol to lysosomes, where endosomal TLRs reside, leading to type-I IFN production. In non-pDCs, autophagy negatively regulates type-I IFN production after viral infection. The Atg5-Atg12 conjugates, which are directly associated with CARD domains of RIG-I and IPS-1, block RLR signaling and suppress type-I IFN production. In another way, autophagy regulates RLR signaling by acting as a scavenger of dysfunctional mitochondria as well as mitochondria-associated IPS-1.

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  Figure 5 Regulation of inflammasome by autophagy. (A) Endotoxin-induced inflammasome activation, mediated by excessive reactive oxygen species, is suppressed by Atg16L1, one of the most important genes involved in Crohn's disease. (B) Autophagy reciprocally regulates the inflammasome activity. The activation of AIM2 or NLRP3 inflammasome triggers autophagy induction by activating RalB to bind to Exo84, which serves as platform for the formation of the isolation membrane. Activation of the inflammasome results in ubiquitination of apoptosis-associated speck-like protein containing a CARD (ASC), and ubiquitinated inflammasomes are engulfed by autophagosomes via adaptor protein p62, which limits IL-1β production by destruction of the active inflammasome.

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