Autophagy and inflammation: A special review issue

ABSTRACT

Macroautophagy/autophagy is a fundamental intracellular homeostatic process that is of interest both for its basic biology and for its effect on human physiology in a wide spectrum of conditions and diseases. Autophagy was first appreciated primarily as a metabolic and cytoplasmic quality control process, but in the past decade its role in immunity has been steadily growing. The connections between these aspects beckon explorations of the network and connections that exist between metabolism, quality control, and inflammation and immunity processes, which are so key to many human diseases including neurodegeneration, obesity and diabetes, chronic inflammatory conditions, cancer, infection, and aging. The purpose of this issue is to stimulate further the burgeoning studies of the intersections between autophagy and inflammation, and the inevitable overlaps with metabolic and quality control functions of autophagy.

The reviews in this issue address autophagy's role in controlling inflammation as a common denominator in a number of health and disease contexts. First, the article by Tooze and Yu introduces the basic mechanisms of autophagy from the perspective of cell biological, membrane trafficking and biochemical processes. This paper is followed by a review from Puertollano and colleagues, which considers the transcriptional mechanisms—including those that involve the MiT/TFR family of transcription factors—that regulate the autophagy-lysosome pathway, and how they intersect with inflammatory disorders.

The initial article in this series that delves into metabolism and inflammation/immune functions is by Simon and colleagues. This review examines how autophagy dictates metabolism in, and differentiation of, inflammatory immune cells. The importance of this topic is underscored by a growing interest in the broader field of immunity in processes collectively termed “immunometabolism;” through autophagy's connections with AMPK and MTOR, which are the key players in immunometabolic phenomena, this topic is a natural link explored in this review.

Next, 2 articles address roles of autophagy and inflammation/immune processes in cancer. Given the ongoing controversy over the roles of autophagy in cancer and an ever-evolving discussion in the field concerning whether inhibition of autophagy during cancer therapy might be beneficial, this is an important topic that benefits, at present, from multiple views. First, the review by Kroemer, Galuzzi and colleagues makes the case for the concept of the benefits of autophagy in cancer immunosurveillance. Next, Monkkonen and Debnath address autophagy as a promoter or suppressor of tumor-associated inflammation and its effects on tumor growth, angiogenesis, invasiveness, and metastasis. In the next 2 reviews, the role of autophagy in general immune system function is examined from 2 angles.

Two articles address the role of autophagy in two major mucosal organ systems: intestinal and respiratory tracts. The first one, by Lassen and Xavier, covers the role of autophagy in intestinal homeostasis, a topic of considerable historic and ongoing interest considering that some of the initial links between autophagy and human disease came from the observations of genetic predispositions to Crohn disease in human populations. This review brings the topic to the next level by not only summarizing what is known but also opening new perspectives. Next, Cloonan, Choi and colleagues, review the role of autophagy and inflammation in lung disease, an area that has not been comprehensively covered previously. Diseases such as chronic obstructive pulmonary disease, asthma, and pulmonary fibrosis are at least in part the result of chronic inflammation of the respiratory tract. The authors examine how autophagy influences these processes, and present the view that whereas autophagy has a beneficial capacity to inhibit spontaneous/endogenous inflammation, its dysregulation in the form of persistent but potentially inefficient activation can lead to pathology and contribute to detrimental outcomes.

The last article that addresses immunity/inflammation in the compilation is by Levine and Deretic. This paper is concerned with the role of autophagy in balancing inflammation in response to infection or sterile inducers of inflammation. The review covers interfaces between autophagy and the inflammasome, as well as autophagy and interferons. It also formulates a parallel model of autophagic response to diverse organellar damage (including mitochondria, lysosomes, and phagosomes) caused by microbes or sterile/endogenous agents, and how this response affects inflammation. The review explores this role of autophagy from the perspective of genetic, functional, and cellular and animal models, and formulates a view for future studies of the intersections between autophagy and innate immunity.

The series concludes with an article by Hansen and colleagues on C. elegans and Drosophila as model systems for the study of autophagy in innate immunity. In particular, this paper highlights the role of autophagy in establishing host tolerance to invasive pathogens. In addition, this review comes full circle by demonstrating how model organisms have been—and will likely continue to be—useful for identifying fundamental aspects of autophagy regulation as it pertains to the immune response including the identification of TFEB as a key regulator of the autophagy-lysosome pathway.

In conclusion, the collection of reviews provides a cross-section of inflammation and related processes as an important aspect of autophagy that is of tremendous significance for human disease. Areas that were not covered conspicuously include neurodegeneration. Whereas there are an overwhelming number of studies connecting autophagy and neurodegenerative diseases such as Alzheimer disease, amyotrophic lateral sclerosis, and ataxias including Huntington and Parkinson diseases, there are only sporadic, but nevertheless telling, hints of inflammatory connections via autophagy. Perhaps this is an area for further growth in the study of neurodegenerative diseases; bridges remain to be made between the less explored inflammatory aspects and metabolism, and the currently emphasized quality control aspects of autophagy.

Funding Statement

This work was supported by the National Institute of General Medical Sciences under Grant [GM053396].