Current Drug Targets   Isabel de Lavera, Ana Delgado Pavón, Marina Villanueva Paz, Manuel Oropesa-Ávila, Mario de la Mata, Elizabet Alcocer-Gómez, Juan Garrido-Maraver, David Cotán, Mónica Álvarez-Córdoba and José A. Sánchez-Alcázar * Centro Andaluz de Biología del Desarrollo [CABD], and Centro de Investigación Biomédica en Red: Enfermedades Raras, Instituto de Salud Carlos III, Universidad Pablo de Olavide-Consejo Superior de Investigaciones Científicas, Sevilla 41013, Spain A R T I C L E H I S T O R Y Received: February 22, 2016 Revised: April 20, 2016 Accepted: April 21, 2016 DOI: 10.2174/1389450117666160527143143 Abstract: Background: The molecular crosstalk between inflammation and autophagy is an emerg- ing field of research that is essential for the understanding of multicellular organism homeostasis and how these processes influence a variety of pathological conditions. Objective: In this review, we briefly describe the relationship between autophagy and inflammasome activation. The central role that mitochondria play in both cellular processes is also discussed. Conclusion: Inflammasome and autophagy often modulate each other by common inhibitory mecha- nisms that are controlled by different input pathways. Thus, inflammasome components coordinate autophagy and autophagy regulates inflammasome activation, making the balance between both proc- esses a fundamental player in cellular homeostasis. Keywords: Autophagy, cytokines, inflammasome, mitochondria, NLRP3, ROS. 1. INFLAMMASOME AND INFLAMMASOME TYPES Multicellular organisms have developed molecular sen- sors to detect pathogens and damaging molecules by intra- cellular receptors, termed pattern recognition receptors (PRRs). PRRs sense pathogen associated molecular patterns (PAMPs) or damage associated molecular patterns (DAMPs) [1, 2]. After detection, PRRs activate the proper defense pathways to preserve cell survival. Four different families of PRRs have been described: C- type lectin receptors (CLRs), retinoic acid-inducible gene (RIG)-I-like receptors (RLRs), Toll-like receptors (TLRs), and nucleotide binding and oligomerization domain (NOD)- like receptors (NLRs), for a complete description, see [3]. In this review we will focus on NLRs, the so-called “inflamma- somes”, the prototypic pathogen/danger-sensing receptors that was first described in detail in 2002 [4]. NLRs are a family of proteins codified by at least 23 human genes re- sponsible for sensing pathogens and damaging molecules [5]. This family of receptors is present in mammals, plants and invertebrates and its structure and function have been extensively studied in mammals [6]. Inflammasome is a cytosolic multiprotein intracellular signaling complex assembled as a consequence of infection, *Address correspondence to this author at the Centro Andaluz de Biología del Desarrollo [CABD]. Universidad Pablo de Olavide-Consejo Superior de Investigaciones Científicas. Carretera de Utrera Km 1, Sevilla 41013, Spain; Tel: 34 954978071; Fax: 34 954349376; E-mail: jasanalc@upo.es. environmental stress or cell damage that participates in the production of pro-inflammatory interleukins (IL) such as IL- 1β and IL-18 and the regulation of the inflammation re- sponse [7, 8]. Additionally to the maturation of pro- inflammatory cytokines, the inflammasome complexes may target different signaling pathways regulating diverse physiological functions such as tissue repair and cell death by pyroptosis [9]. Numerous inflammasomes have been identified so far, including NLRs such as NLRP1, NLRP2, NLRP3, NLRC4 and double-stranded DNA (dsDNA) sensors absent in mela- noma 2 [AIM2] and interferon-inducible protein-16 (IFI-16) [10, 11]. AIM2 and interferon-inducible protein-16 (IFI-16) are structurally different to the other NLRs, although they are functionally related. The mechanisms of activation of the different types of in- flammasomes have been recently reviewed [12]. Most NLRPs have a common molecular organization formed by three main functional domains: an Nterminal CARD or PYRIN (PYD) protein interaction domain; a central nucleo- tide-binding domain [NBD] for oligomerisation; and C- terminal leucine-rich repeats (LRRs), for pathogen sensing [13]. AIM2 and IFI16 belonging to the PYHIN (PYD and HIN domain-containing proteins) family. AIM2 has one DNA-binding HIN domain for detecting nucleic acids, and a PYD domain to interact with ASC [14]. IFI16 has one PYD and two HIN domains, and signals through STING [for stimulator of interferon genes] to regulate type I IFN re- 1873-5592/17 $58.00+.00 © 2017 Bentham Science Publishers Send Orders for Reprints to reprints@benthamscience.ae 1030 Current Drug Targets, 2017, 18, 1030-1038 REVIEW ARTICLE The Connections Among Autophagy, Inflammasome and Mitochondria