Inflammasome and Autophagy Regulation: A Two-way Street

Qian Sun,1 Jie Fan,1,2 Timothy R Billiar,1 and Melanie J Scott1

1Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America; and 2Research and Development, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania, United States of America

Inflammation plays a significant role in protecting hosts against pathogens. Inflammation induced by noninfectious endogenous agents can be detrimental and, if excessive, can result in organ and tissue damage. The inflammasome is a major innate immune pathway that can be activated via both exogenous pathogen-associated molecular patterns (PAMPs) and endogenous damage-associated molecular patterns (DAMPs). Inflammasome activation involves formation and oligomerization of a protein complex including a nucleotide oligomerization domain (NOD)-like receptor (NLR), an adaptor protein and pro-caspase-1. This then allows cleavage and activation of caspase-1, followed by downstream cleavage and release of proinflammatory cytokines interleukin (IL)-1β and IL-18 from innate immune cells. Hyperinflammation caused by unrestrained inflammasome activation is linked with multiple inflammatory diseases, including inflammatory bowel disease, Alzheimer’s disease and multiple sclerosis. So there is an understandable rush to understand mechanisms that regulate such potent inflammatory pathways. Autophagy has now been identified as a main regulator of inflammasomes. Autophagy is a vital intracellular process involved in cellular homeo- stasis, recycling and removal of damaged organelles (eg, mitochondria) and intracellular pathogens. Autophagy is regulated by proteins that are important in endosomal/phagosomal pathways, as well as by specific autophagy proteins coded for by auto- phagy-related genes. Cytosolic components are surrounded and contained by a double-membraned vesicle, which then fuses with lysosomes to enable degradation of the contents. Autophagic removal of intracellular DAMPs, inflammasome components or cytokines can reduce inflammasome activation. Similarly, inflammasomes can regulate the autophagic process, allowing for a two-way mutual regulation of inflammation that may hold the key for treatment of multiple diseases. Online address: http://www.molmed.org doi: 10.2119/molmed.2017.00077

INTRODUCTION of recent research has focused on how autophagy in an attempt to protect the Inflammatory innate immune responses inflammasomes are activated and how host from excessive inflammation (7). are important in host defense against their activation is regulated, and this has This mutual regulation is important to pathogens (1,2). Similar pathways can be led to a new appreciation of the interreg- understand, as it applies to multiple activated by sterile exogenous or endog- ulation of inflammasomes and autophagy. disease processes, and in this review we enous agents, but the resulting inflam- Autophagy is an intracellular process discuss currently available information mation can be detrimental through the important for cellular homeostasis and about the two-way street of regulation induction of organ and tissue damage, recycling of damaged organelles and that exists between inflammasomes and resulting in inflammatory disease (2,3). proteins, as well as destruction of intra- autophagy. One of the main inflammatory pathways cellular pathogens (4). In diseases where leading to disease involves activation autophagy is restricted or diminished Activation of Inflammasomes of the inflammasome, a multiprotein (eg, inflammatory bowel disease), there Inflammasomes are cytosolic multi- complex that initiates inflammatory is hyperinflammation and hyperactiva- protein platforms assembled in response responses to both pathogen and endoge- tion of inflammasomes (5,6). Similarly, to wide-ranging stimuli, including nous activators (3). Understandably, a lot inflammasome activation can upregulate pathogen-associated molecular patterns (PAMPs) and damage-associated mo- lecular patterns (DAMPs) (1). A typical inflammasome contains a sensor protein Address correspondence to Melanie J Scott, Department of Surgery Labs, University of belonging either to the nucleotide oligo- Pittsburgh, NW653 MUH, 3459 Fifth Ave, Pittsburgh, PA 15213. Phone: 412-647-5806; merization domain (NOD)-like receptor Fax: 412-647-5959; E-mail: [email protected]. (NLR) nucleotide-binding domain (NBD) Submitted May 2, 2017; Accepted for Publication July 20, 2017; and leucine-rich repeat (LRR)-containing Published Online (www.molmed.org) July 24, 2017. family or the absent in melanoma 2 (AIM2)-like receptor (ALR) family of pattern recognition receptors; an adaptor protein, apoptosis-associated speck-like

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(ASC) protein, containing a caspase- and pyrin domain–containing 1 (NLRP1); include both pathogenic microorganisms recruitment domain; and pro-caspase-1 NLRP3; NOD-, LRR- and caspase recruit- and endogenous mediators, such as reac- (8). Activation of these inflammasome ment domain–containing 4 (NLRC4); tive oxygen species (ROS), mitochondrial complexes results in proteolytic cleavage and AIM2, a sensor for nucleic acids DAMPs and adenosine triphosphate of zymogen pro-caspase-1 into its enzy- (Figure 1) (9). NLRP1 and NLRC4 in- (ATP), as well as by crystalline structures matically active form, which then leads flammasomes are activated by specific (eg, uric acid crystals) and other fibrillar to maturation of proinflammatory cyto- PAMPs, such as muramyl dipeptide and proteins (eg, β-amyloid fibrils) and envi- kines interleukin (IL)-1β and IL-18 (9). flagellin, respectively (2). The NLRP3 ronmental irritants (eg, silica, alum) (10). Four main inflammasomes have been inflammasome is interesting, as it can be AIM2 responds specifically to double- identified: NLR members NOD-, LRR- activated by a wide range of stimuli that stranded DNA (dsDNA), which can be

Figure 1. Canonical and noncanonical inflammasomes. A typical inflammasome contains a sensor protein belonging to either the NLR or ALR family of pattern recognition receptors, an adaptor protein ASC and pro-caspase-1. NAIP-NLRC4 is activated by bacterial flagellin and type III secretion system proteins, NLRP1 is activated by lethal toxin and muramyl dipeptide, AIM2 is activated by cytosolic dsDNA and NLRP3 is activated by a variety of activators including ATP, uric acid, alum, β-amyloid, MSU and nigericin. Activation of these inflammasome complexes results in proteolytic cleavage of zymogen pro-caspase-1 into its enzymatically active form, which then leads to maturation of proinflammatory cytokines IL-1β and IL-18. In the noncanonical inflammasome pathway, pro-caspase-11 expression is induced by a variety of Toll-like receptor ligands, or via type I interferon signaling. Caspase-11 is self-oligomerized and activated by cyto- solic LPS, which subsequently leads to caspase-1 activation, as well as gasdermin D–mediated pyroptotic cell death in macrophages.

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derived either from host (nucleic and genes (Atg) (4,14). Autophagy plays an related 16-like 1 (Atg16L1), a protein mitochondrial dsDNA) or from patho- important role in multiple biological essential for initiation of autophagy, gen (3). Recent work has shown that in processes, including cell metabolism, results in increased caspase-1 activation, most cases, activation of individual NLR cellular development and differentiation, as well as increased production of IL-1β inflammasomes is relatively specific, and degenerative diseases, and also in and IL-18 in macrophages after endo- but can only occur in response to such pathology related to aging (14). The ini- toxin treatment (17). Similarly, IL-1β wide-ranging stimuli through direct as- tiation of autophagy in response to cell production in macrophages deficient sociation with select protein mediators. starvation and the reduced availability in autophagic protein Atg7, or treated This explains why evidence of direct of amino acids highlights its role in cell with a chemical inhibitor of autophagy interaction between inflammasome acti- homeostasis and metabolism. Much of 3-methyladenine (3-MA), is significantly vators and NLRs was lacking for such a this is regulated through the inhibition of enhanced in response to inflammasome long time (1,3). NLRC4 is activated after mammalian target of rapamycin (mTOR) inducers (17). Later studies further indi- binding of individual neuronal apoptosis (15), but autophagy can also be induced cated that regulation of inflammasome inhibitory protein (NAIP) family mem- by organelle stress and intracellular infec- activation by autophagy can occur in bers, which bind specifically to NLRC4 tion, and can induce both protective and multiple ways, through either removal activators such as flagellin and type III cell death pathways (16). of endogenous inflammasome activators secretion system proteins (11). Similarly, or removal of inflammasomes and their NLRP3 is activated through association Autophagy Regulation of downstream cytokines directly (Figure 2). with Nek7, which is able to bind in re- Inflammasome Activation sponse to activation by multiple NLRP3 Saitoh et al. were the first to show Autophagic Removal of activators that cause a drop in intracel- that autophagy can negatively regulate Mitochondrial-Derived DAMPs lular potassium levels (12). Even AIM2, inflammasome activation, and this was Autophagy removes damaged organ- which has been shown to directly bind followed by multiple studies showing elles such as mitochondria, leading to dsDNA for activation, is able to use high similar effects in a variety of experimen- reduced release of mitochondrial-derived mobility group box 1 (HMGB1) to en- tal systems (17,18) (Table 1). The initial DAMPs and subsequent suppression hance activation and regulate its activa- study showed that loss of autophagy- of inflammasome activation (19–21). tion in response to redox stress through differences in the affinity of HMGB1 Table 1. Autophagy regulation of inflammasome activation. binding in different oxidized states (13). Manipulation In general, however, inflammasome of Autophagy Inflammasome Downstream Signaling activation is regulated by the levels of Pathway Activator Pathway Cell Type References activating stimuli, be they endogenous or Loss of LPS ↑ caspase 1 activation Macrophage (17) exogenous, as well as the availability of Atg16L1 ↑ IL-1β/IL-18 production individual inflammasome components, Loss of Atg7 LPS ↑ caspase 1 activation Macrophage (17,23,37) which are kept at low levels of expres- Viral RNA ↑ IL-1β production sion in innate immune responders such Alum as macrophages (3). Nigericin Loss of Atg5 LPS ↑ caspase 1 activation Macrophage (19,40) Multifaceted Roles for Autophagy MSU ↑ IL-1β production Autophagy is a vital intracellular Nigericin Loss of beclin1 LPS ↑ mtDNA release Macrophage (19,20) homeostatic recycling process (4). Cytoso- MSU ↑ caspase 1 activation lic components, including overproduced Nigericin ↑ IL-1β production or misfolded proteins, cellular organelles Loss of LC3B LPS + ATP ↑ caspase 1 activation Macrophage (20) (eg, mitochondria) or even pathogenic ↑ IL-1β production cytosolic bacteria, are packaged into 3-MA LPS ↑ NLRP3 activation Macrophage (19,38) double-​membraned autophagosomes and ↑ caspase 1 activation Dendritic cells delivered to lysosomes for degradation ↑ IL-1β production and recycling of amino acids (4). The pro- Rapamycin Poly(dA:dT) ↓ AIM2 activation Macrophage (31,39) cess of autophagy is regulated by a large ↓ caspase 1 activation Non-parenchymal number of proteins that are also import- ↓ IL-1β production cells ant in endosomal and phagosomal path- Starvation Poly(dA:dT) ↓ AIM2 activation Macrophage (31) ↓ caspase 1 activation ways, as well as by specific autophagy ↓ IL-1β production proteins coded for by autophagy-­related

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Figure 2. Inflammasome and autophagy interregulation. Autophagy can negatively regulate inflammasome activation by removing mitochondrial-derived DAMPs as well as through selective degradation of inflammasome complexes and mitochondria. Autophagy ­machinery also directly regulates IL-1β activation, release and signaling. Conversely, inflammasome activation regulates autophago- some formation through direct or indirect interactions.

Zhou et al. demonstrated that following studies, by Nakahira et al. and Shimada translocation of mtDNA, leading to pharmacological inhibition of mitochon- et al., suggest that following the produc- greatly enhanced activation of caspase-1 drial complex I and III, increased mito- tion of mitochondrial ROS and loss of mi- and downstream cytokine release (20). chondrial ROS production is responsible tochondrial integrity, cytosolic release of It is not yet fully understood how mi- for NLRP3-mediated caspase-1 activation mitochondrial DNA (mtDNA) is respon- tochondrial ROS contribute to NLRP3 and IL-1β release in monocytes, which sible for activating NLRP3 inflammasome inflammasome activation and how the can be further reversed by ROS scavenger (20,21). Furthermore, oxidized mtDNA process is regulated by autophagy. Sev- (19). Similarly, loss of autophagy results was shown to activate NLRP3 inflam- eral steps remain to be fully elucidated. in accumulation of ROS-producing mi- masome to a greater extent than regular First, reduction of autophagy by itself tochondria, and subsequently enhanced mtDNA, suggesting that both mitochon- does not seem to be sufficient to trigger activation of NLRP3 inflammasome in drial ROS and mtDNA are important for inflammasome activation in the absence of response to NLRP3 agonist ATP, mono- NLRP3 activation (21). Disruption of au- NLRP3 inducers (19,20). Second, since mi- sodium urate crystals, palmitic acid or tophagy in this process impairs mitochon- tochondrial ROS are normal byproducts of influenza A virus (19,20,22,23). Two other drial homeostasis and promotes cytosolic mitochondrial respiration, it is unknown

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whether NLRP3 can sense ROS generated radation of ­inflammasome complexes of autophagy that inhibits mTOR (38). from intact mitochondria as a result of in- and mitochondria. Upon stimulation of This pathway therefore contributes to creased mitochondrial metabolism. More- AIM2 and NLRP3 inflammasomes, K63 autophagy-mediated reduction in IL-1β over, ROS are short-lived molecules and (Lys 63)-linked polyubiquitination of ASC secretion in response to NLRP3 inducers can be scavenged by intracellular antioxi- is triggered, which is then recognized by (38). However, two other studies suggest dants such as glutathione and thioredoxin, ubiquitin sensor p62, and ASC is targeted that autophagy is actually required for so it is possible that the availability of an- to autophagosomes for degradation (31). the unconventional secretion of IL-1β, tioxidants is another important regulatory Both pharmacological inhibition of auto- and reducing autophagy can lead to re- factor (24). Additionally, caspases (includ- phagy and loss of p62 can greatly increase duced IL-1β release in response to AIM2 ing caspase-1) can be post-translationally activation of caspase-1 and inflammatory and NLRP3 activators in macrophages modified (eg, by S-­nitrosylation and cytokine production in response to AIM2 (39,40). In one of the studies, Wang ubiquitination) (25–27) in processes that inducer poly(dA:dT) in monocytes (31). et al. showed that autophagy-dependent may be influenced by redox status and an- AIM2 can also undergo ubiquitination secretion of IL-1β after AIM2 inflamma­ tioxidant availability. These modifications and be degraded by p62-dependent se- some activation required microtubule-­ can affect not only caspase activity (28,29), lective autophagy in macrophages upon associated protein end-binding protein 1 but also degradation (27) and so reduce poly(dA:dT) treatment (32). Tripartite (39). Disruption of autophagy by inhibi- cytokine cleavage and release following motif 11, an E3 ubiquitin ligase, was tion of AMPK activity was able to block inflammasome activation. Although shown to associate with AIM2 and facili- poly(dA:dT)-induced AIM2-mediated the exact mechanism of ROS-­mediated tate its recruitment to p62 for autophagic IL-1β secretion (39). Dupont et al. also NLRP3 inflammasome activation remains degradation (32,33). Supporting this notion demonstrated that induction of autoph- unclear, several hypotheses have been of ubiquitination of inflammasome result- agy by starvation triggered increased tested. The first hypothesis suggests that ing in degradation as a form of regulation, secretion of IL-1β in response to nigeri- upon activation of the NLRP3 inflam- TRIM20 was also shown in a separate cin, an NLRP3 inflammasome activator masome by its agonist nigericin, monoso- study to target a group of inflammasome (40). A similar unconventional secretory dium urate crystals or alum (aluminum components for autophagic degradation in pathway also contributes to the extracel- hydroxide and aluminum phosphate macrophages, including NLRP3, NLRP1 lular delivery of another inflammasome adjuvants), NLRP3 translocates to mito- and pro-caspase-1 in response to IFN-γ activated cytokine, IL-18 (40). At present, chondria and mitochondria-­associated en- stimulation (34). In addition to target- it is not clear why there is a discrepancy doplasmic reticulum membranes (MAMs), ing inflammasome proteins themselves, in the results between data showing placing it in proximity to newly generated dysfunctional mitochondria can also be autophagy inducing and reducing IL-1β mitochondrial ROS (19). Another hy- marked with ubiquitin and tagged for release. The regulatory effect of autoph- pothesis involves the interaction between autophagic disposal (35). During this pro- agy on IL-1β release is obviously compli- thioredoxin-interacting protein (TXNIP) cess, another E3 ubiquitin, ligase parkin, cated and requires further investigation, and NLRP3, which has been shown is essential for the ubiquitination of outer and may be dependent on cell type and to be crucial for redox stress-­mediated mitochondrial membrane proteins and ­inducer/activator. inflammasome activation (30). In this subsequent selective degradation of dam- scenario, TXNIP translocates to MAMs/ aged mitochondria, or mitophagy (35,36). Inflammasome Regulation of mitochondria following NLRP3 activation A recent study by Zhong et al. suggested Autophagy in a ROS-dependent manner, allowing its that a parkin-dependent clearance of p62- Regulation of autophagy by NLRs. potential binding to NLRP3 (19). However bound mitochondria can reduce NLRP3 NLR inflammasomes are the most the NLRP3 inflammasome is activated, it activation and IL-1β release in macro- well-studied inflammasomes, and include seems likely that a prolonged presence of phages (37), providing another mechanism NLRP1, NLRP3 and NLRC4 (previously damaged and ROS-producing mitochon- for autophagy-​mediated inhibition of known as IPAF) (9). Most NLR proteins dria is necessary to trigger activation, and ­inflammasome activation. contain an amino-terminal death-fold by removing dysfunctional mitochondria, domain caspase recruitment domain autophagy functions to reduce excessive Autophagy and IL-1a Signaling or pyrin, a central domain nucleotide-­ activation of the NLRP3 inflammasome. Last but not least, autophagy machin- binding domain (NACHT, or NAIP, ery directly regulates IL-1β activation, re- CIITA, HET-E and TP1), as well as LRRs Selective Autophagy in lease and signaling. Harris et al. showed at the carboxy terminus (10). These do- Inflammasome Activation that pro-IL-1β can be sequestered into mains allow NLRs to oligomerize and to Another mechanism by which au- autophagosomes for degradation fol- interact with other inflammasome pro- tophagy regulates inflammasome acti- lowing treatment of macrophages with teins with similar domains to form large vation is through p62-dependent deg- rapamycin, a pharmacological inducer inflammasomeultrastructures ­ that have a

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prion-like appearance and can even be vi- to persistent Citrobacter rodentium infec- has now been confirmed in two separate sualized at times by light microscopy (41). tion (46). Another example is a role for models (13,52). In the first model, AIM2 Interaction of autophagy proteins with NLRP3 inflammasome in the promotion activation by host-derived dsDNA led to NLR domains has also been reported, and of autophagy following Pseudomonas increased autophagic flux in hepatocytes provides a mechanism for direct NLR reg- aeruginosa infection in macrophages (47). after redox stress induced by hypoxia ulation of autophagy (Figure 2). In this case, NLRP3-mediated autoph- with reoxygenation (13). Moreover, in Jounai et al. recently suggested that agy is important for bacterial clearance vivo induction of autophagy by AIM2 in- a number of inflammasome-forming in these cells. Autophagy regulation by flammasome was protective by inducing and non-inflammasome–forming NLRs NLRs therefore seems to differ depend- removal of ROS-generating mitochondria can interact with beclin1, a protein ing on the cell type under investigation in the liver (13,53). Similar to the previ- important in autophagy initiation, via and the conditions leading to autophagy ous study with RalB, beclin1 was an im- the NACHT domain (42). Among these or inflammasome activation. portant mediator in autophagy activation NLRs, NLRP4 (an NLR not known to Regulation of autophagy by ALRs. mediated by AIM2 (13,53). In contrast, in form inflammasomes) in particular has ALR inflammasomes include AIM2 and hepatocytes, AIM2-­dependent regulation a strong affinity to beclin1, and this in- IFI16 inflammasomes, which have also of autophagy was mediated by caspase-1, teraction leads to autophagy inhibition been studied in multiple cell types and suggesting that mechanisms of AIM2-­ (42). Following group A Streptococcus multiple experimental models. Unlike mediated autophagy regulation may dif- infection, NLRP4 transiently dissociates NLRs, ALRs can directly associate with fer between immune and nonimmune cell from beclin1, allowing it to interact with their ligand, dsDNA, through a HIN200 types (53,54). In the second model, Saiga other autophagy proteins to initiate domain (1). Recognition of microbial DNA et al. demonstrated that following infec- beclin1-mediated autophagy in mac- by AIM2 and IFI16 triggers production of tion of recombinant bacillus Calmette- rophages (42). Inflammasome-forming proinflammatory cytokines IL-1β and IL- Guerin, a live attenuated vaccine against NLRP3 has also been shown to neg- 18, and this drives host defense responses tuberculosis, autophagy induction was atively regulate autophagy through to a number of intracellular microbes, in- partially dependent on AIM2 in macro- downregulation of phosphatase and cluding Francisella, Listeria, Mycobacterium phages (52). Therefore, it seems that acti- tensin homolog–induced putative kinase sp., mouse cytomegalovirus and Kaposi vation of AIM2 inflammasome, by either 1 expression, an initiator of mitophagy sarcoma–­associated herpesvirus (48,49). microbial or endogenous self-DNA, trig- (43). Zhang et al. demonstrated that NL- On the other hand, ­host-­derived dsDNA gers host adaptive autophagy responses RP3-deficient mice were protected from can also be recognized by AIM2, such designed to limit excessive inflammation hyperoxia exposure, and this protection as in a model of whole-body irradiation and ­restore cellular homeostasis. was driven by increased phosphatase (50), leading to sustained inflammation Regulation of autophagy by and tensin homolog–induced putative and resulting in the development of in- caspase-1. Caspase-1 is a key compo- kinase 1 expression and preservation of flammatory diseases such as dermatitis nent of inflammasome and has been mitophagy in lung endothelial cells of and psoriasis (48). In addition to the reported to regulate the autophagic pro- these mice (43). In addition to NLRP3, cytokine-­maturation role of ALRs, recent cess through proteolytic cleavage of its NLRC4 can also inhibit autophagy in studies have begun to implicate ALRs as substrates (55,56). Yu et al. showed that infection (44). In response to Shigella regulators of cytoprotective ­autophagy caspase-1 activation can result in cleav- infection, autophagy was significantly responses. age of a key mitophagy regulator, parkin, increased in NLRC4-deficient mac- Shi et al. were the first to show that thereby decreasing mitophagy and in- rophages, and this NLRC4-mediated induction of AIM2 inflammasomes with creasing the numbers of damaged mito- inhibition was dependent on caspase-1 synthetic dsDNA poly(dA:dT) triggers chondria in the cell after AIM2 activator (44,45), although the exact mechanism increased autophagosome formation in dsDNA (55). These damaged mitochon- of NLRC4/caspase-1 regulation of macrophages (31). Upon activation of dria have alterations in ­mitochondrial ­autophagy remains unknown. AIM2, a Ras-like small G-protein, RalB, permeability transition/depolarization, Conversely, there is also evidence to is activated, which then induces the as- increased mitochondrial ROS production suggest that NLRs can stimulate auto- sembly of autophagy initiation ­complexes and swelling, and this allows further phagosome formation. NLRP6, another containing beclin1 (31,51). Interestingly, inflammasome activation and inflam- non-inflammasome–forming NLR, is in this case, induction of autophagy matory pyroptotic cell death in bone crucial for autophagy in intestinal epi- is not dependent on caspase-1 or the marrow–derived macrophages (55). In thelial cells (46). Deletion of NLRP6 in adaptor protein ASC, as the phenotype another study, caspase-1 was demon- mice results in impaired autophagy in cannot be recapitulated in caspase-1 strated to cleave Toll/interleukin-1­ the gut, with impaired mucus secretion, or ASC-­deficientmacrophages­ (31). receptor domain-containing adapter-­ which makes the mice highly susceptible AIM2-mediated activation of ­autophagy inducing interferon-β (TRIF), leading to

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downregulation of TRIF-mediated auto- suggesting that autophagy is a negative inducing inflammation, inflammasome phagy following Pseudomonas aeruginosa regulator of caspase-11 activation (61). activation and autophagy. This highly infection (56). Moreover, expression of Although the underlying mechanisms variable response surely signifies an ulti- a caspase-resistant TRIF mutant signifi- of autophagy regulation of caspase-11 mately adaptable response that we may cantly increased autophagy in infected activation remain largely unclear, it is be able to manipulate in the future to pro- macrophages. Therefore, proteolytic may be that autophagy inhibits activa- vide relief for millions of patients suffer- cleavage of key autophagic regulatory tion of caspase-11 by removing excessive ing from degenerative, inflammatory or proteins by caspase-1 can lead to loss of mitochondrial ROS, as these were sug- tumorigenic disease – or even for the rest function of these substrates and defective gested to enhance caspase-11 expression of us, who are merely steadily aging. autophagy, particularly in immune cells. and activation (62). On the other hand, However, similar to other aspects of in- noncanonical inflammasome activation ACKNOWLEDGMENTS flammasome-autophagy interregulation, also seems to regulate levels of auto- Work performed for this paper was sup- the effects of caspase-1 activation seem phagy machinery expression. A study ported by NIH-R01-GM102146 (to MJS). to be cell type–specific, and also poten- by Akhter et al. describes the ability of tially experimental model or caspase-1 caspase-11 to promote fusion of lyso- DISCLOSURE ­activator–dependent. somes with ­bacteria-containing phago- The authors declare they have no com- Noncanonical activation of inflam- somes, providing a role for caspase-11 in peting interests as defined by Molecular masome and autophagy. Recent evidence antibacterial autophagy (63,64). Specifi- Medicine or other interests that may be suggests that caspase-1 activation can cally, upon bacterial infection, caspase-11 perceived to influence the results and occur in response to LPS (endotoxin), a promotes dynamic formation of polym- discussion reported in this paper. key component of Gram negative bac- erized actin around phagosomes, which teria, independent of canonical inflam- is required for phagosome-­lysosome fu- REFERENCES masomes (57). 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