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Inflammasome Activation Leads to Caspase-1– Dependent Mitochondrial Damage and Block of Mitophagy

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Inflammasome Activation Leads to Caspase-1– Dependent Mitochondrial Damage and Block of Mitophagy Inflammasome activation leads to Caspase-1– dependent mitochondrial damage and block of mitophagy Jiujiu Yua,1,HajimeNagasua,1, Tomohiko Murakamia,2, Hai Hoanga, Lori Broderickb,c, Hal M. Hoffmanb,c, and Tiffany Hornga,3 aDepartment of Genetics & Complex Diseases, Harvard School of Public Health, Boston, MA 02115; bDepartment of Pediatrics, University of California, San Diego, La Jolla, CA 92093; and cRady Children’s Hospital, San Diego, CA 92123 Edited by Ruslan Medzhitov, Yale University School of Medicine, New Haven, CT, and approved September 22, 2014 (received for review August 4, 2014) Inflammasomes are intracellular sensors that couple detection of niche (12), as well as other settings (13, 14), but experimental pathogens and cellular stress to activation of Caspase-1, and con- demonstration of its physiological role is hampered by the lack of sequent IL-1β and IL-18 maturation and pyroptotic cell death. Here, mechanistic insights into its regulation. Pyroptosis shares some we show that the absent in melanoma 2 (AIM2) and nucleotide- features with necrosis (such as loss of plasma-membrane integrity binding oligomerization domain-like receptor pyrin domain-contain- and release of intracellular contents) and others with apoptosis ing protein 3 (NLRP3) inflammasomes trigger Caspase-1–dependent (including DNA fragmentation and nuclear condensation) (12). mitochondrial damage. Caspase-1 activates multiple pathways to Mitochondrial damage critically underlies apoptosis mediated by precipitate mitochondrial disassembly, resulting in mitochondrial initiator caspases like Caspase-8 and Caspase-9. Upon activation reactive oxygen species (ROS) production, dissipation of mitochon- by death receptors, Caspase-8 cleavage of the protein Bid precip- drial membrane potential, mitochondrial permeabilization, and itates mitochondrial outer membrane permeabilization (MOMP), fragmentation of the mitochondrial network. Moreover, Caspase-1 resulting in dissipation of the membrane potential, disruption inhibits mitophagy to amplify mitochondrial damage, mediated in of mitochondrial function, and release of apoptosis-promoting part by cleavage of the key mitophagy regulator Parkin. In the ab- factors from the intermembrane space (15). MOMP can also lead to mitochondrial permeability transition (MPT), or breach of in- sence of Parkin activity, increased mitochondrial damage augments tegrity of the inner membrane caused by opening of an inner pyroptosis, as indicated by enhanced plasma membrane perme- membrane pore, which further amplifies mitochondrial damage abilization and release of danger-associated molecular patterns (16). Whether mitochondrial damage contributes to pyroptosis and (DAMPs). Therefore, like other initiator caspases, Caspase-1 activa- in general how pyroptosis is regulated, including the relevant tion by inflammasomes results in mitochondrial damage. substrates, are not clear. inflammasomes | mitochondrial damage | pyroptosis | mitophagy Results Amplification of Mitochondrial Damage by the NLRP3 Inflammasome. nflammasomes are cytosolic complexes that mediate Caspase-1 Recent studies suggest that mitochondrial damage may or may Iactivation in response to pathogen infection and cellular stress not be triggered by the NLRP3 inflammasome (9, 11). Here, we (1, 2). They consist of a regulatory subunit, which couples stimulus decided to reexamine this issue using additional stimuli, extended recognition to complex assembly; Caspase-1, the effector subunit; time courses, and several readouts of mitochondrial damage. and the adaptor protein Asc. The best-characterized inflamma- somes include the AIM2 inflammasome, which detects cytosolic Significance DNA during bacterial and viral infection, and the NLRP3 inflammasome, which is activated by many stimuli in a variety of Sensors of the innate immune system trigger the induction of in- settings including infection and metabolic inflammation. Although flammatory responses upon infection and cellular stress. One such not entirely clear, one plausible model of NLRP3 inflammasome sensor is the inflammasome pathway, which is best described for activation is the generation of some mitochondria-associated signal its role in the production of the inflammatory cytokines IL-1β and by mitochondrial destabilization (3, 4). Recruitment of Cas- IL-18. Other effector functions of the inflammasome pathway re- pase-1 into the inflammasome complex leads to its activation, main less well defined, and here we show that activation of this autoprocessing, and subsequent substrate cleavage. pathway leads to induction of mitochondrial damage and dis- The prototypical inflammasome-mediated functions are IL-1β mantling of the organelle. We link such mitochondrial damage to and IL-18 maturation and induction of pyroptosis (1). Additionally, another inflammasome-regulated process called pyroptosis, which inflammasomes control other processes like unconventional se- is a proinflammatory form of cell death. In summary, we charac- cretion of intracellular proteins (5), such as DAMPs like high terize the role of mitochondrial damage during activation of the mobility group box 1 (HMGB1) (6), and regulation of autophagy inflammasome pathway, of relevance to host defense and other (7, 8). These examples suggest the existence of additional inflam- physiological and pathophysiological settings. masome effector activities that are likely to vary in a context- dependent manner. Interestingly, a recent report indicated that ac- Author contributions: T.H. designed research; J.Y., H.N., T.M., H.H., and L.B. performed re- tivation of the NLRP3 inflammasome by extracellular ATP leads to search; H.M.H. contributed new reagents/analytic tools; J.Y., H.N., T.M., L.B., H.M.H., and T.H. NLRP3-dependent dissipation of the mitochondrial membrane po- analyzed data; and T.H. wrote the paper. tential (9), but subsequent studies proposed that such mitochondrial The authors declare no conflict of interest. damage is solely a trigger of inflammasome activation (10, 11) be- This article is a PNAS Direct Submission. cause it occurs normally in the absence of the NLRP3 inflamma- 1J.Y. and H.N. contributed equally to this work. some (11). Thus, the relationship between NLRP3 inflammasome 2Present address: Department of Molecular and Cellular Biochemistry, Osaka University activation and mitochondrial damage remains unclear. Graduate School of Dentistry, 1-8 Yamada-Oka, Suita, Osaka 565-0871, Japan. Pyroptosis is a Caspase-1–mediated, proinflammatory form of 3To whom correspondence should be addressed. Email: [email protected]. cell death. It occurs during infection by many intracellular patho- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. gens where it can critically eliminate an intracellular replication 1073/pnas.1414859111/-/DCSupplemental. 15514–15519 | PNAS | October 28, 2014 | vol. 111 | no. 43 www.pnas.org/cgi/doi/10.1073/pnas.1414859111 Downloaded by guest on September 28, 2021 AB mitochondrial damage, as indicated by Caspase-1–dependent de- polarization and mROS induction (Fig. S1 D–F). Of note, ATP and nigericin treatment seemed to directly perturb mitochon- drial physiology in all/most WT BMDMs [e.g., inflammasome- independent increases in mROS production (Fig. 1A and Fig. S1C) or hyperpolarization (Fig. 1B and Fig. S1 C and E)]. In contrast, inflammasome-mediated amplification of mitochondrial damage was observed only in a subset of WT cells [e.g., mROS production (Fig. 1A and Fig. S1F) or depolarization (Fig. 1B and Fig. S1 B, D, and E)], which may reflect inflammasome activation only in those cells (consistent with single-cell analysis of inflammasome activa- tion in other studies) (17). These findings support the model that CDNLRP3 inflammasome activators engage mitochondrial destabiliza- tion via stimulus-specific mechanisms (e.g., increased mROS pro- duction by ATP but not nigericin) that converge on generation of some signal associated with mitochondrial damage, leading to in- flammasome activation and Caspase-1–dependent escalation of mitochondrial damage. No defect in mitochondrial damage was −/− observed in Casp11 BMDMs (Fig. S1G); thus, we attribute −/− −/− defects in Casp1 Casp11 BMDMs throughout this study to Caspase-1. Instigation of Mitochondrial Damage by the AIM2 Inflammasome. Fig. 1. The NLRP3 inflammasome amplifies mitochondrial damage. LPS- These findings led us to hypothesize that inflammasomes other primed BMDMs of the indicated genotypes were stimulated with ATP, fol- than NLRP3 may trigger Caspase-1–dependent mitochondrial lowed by staining with MitoSox (gray line, WT unstimulated; black line, WT; dashed line, Casp1−/−Casp11−/−)(A), Mitotracker Green and Mitotracker Deep Red (B), or AV/PI (C), or analysis in LDH release assay (D). In B, gated cells stain less brightly with Mitotracker Deep Red (i.e., downward shift), indicative of −/− −/− −/− AB loss of ΔΨm.InD, * indicates P < 0.05 relative to Casp1 Casp11 and Nlrp3 BMDMs (n ≥ 3). Consistent with previous reports, ATP treatment of lipopoly- saccharide (LPS)-primed bone marrow-derived macrophages (BMDMs) triggered rapid changes to mitocondrial ROS (mROS) production and membrane potential (ΔΨm). Impor- tantly, such changes were largely but incompletely dependent on the NLRP3 inflammasome. ATP triggered an initial increase in C mROS production that is evident in the time-dependent −/− −/− increases in MitoSox staining in WT, Nlrp3 , and Casp1 −/− Casp11 BMDMs whereas, at later time points, further −/− increases
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