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• W2076062022 abstract "Autophagy is a key regulator of cellular homeostasis that can be activated by pathogen-associated molecules and recently has been shown to influence IL-1β secretion by macrophages. However, the mechanisms behind this are unclear. Here, we describe a novel role for autophagy in regulating the production of IL-1β in antigen-presenting cells. After treatment of macrophages with Toll-like receptor ligands, pro-IL-1β was specifically sequestered into autophagosomes, whereas further activation of autophagy with rapamycin induced the degradation of pro-IL-1β and blocked secretion of the mature cytokine. Inhibition of autophagy promoted the processing and secretion of IL-1β by antigen-presenting cells in an NLRP3- and TRIF-dependent manner. This effect was reduced by inhibition of reactive oxygen species but was independent of NOX2. Induction of autophagy in mice in vivo with rapamycin reduced serum levels of IL-1β in response to challenge with LPS. These data demonstrate that autophagy controls the production of IL-1β through at least two separate mechanisms: by targeting pro-IL-1β for lysosomal degradation and by regulating activation of the NLRP3 inflammasome. Autophagy is a key regulator of cellular homeostasis that can be activated by pathogen-associated molecules and recently has been shown to influence IL-1β secretion by macrophages. However, the mechanisms behind this are unclear. Here, we describe a novel role for autophagy in regulating the production of IL-1β in antigen-presenting cells. After treatment of macrophages with Toll-like receptor ligands, pro-IL-1β was specifically sequestered into autophagosomes, whereas further activation of autophagy with rapamycin induced the degradation of pro-IL-1β and blocked secretion of the mature cytokine. Inhibition of autophagy promoted the processing and secretion of IL-1β by antigen-presenting cells in an NLRP3- and TRIF-dependent manner. This effect was reduced by inhibition of reactive oxygen species but was independent of NOX2. Induction of autophagy in mice in vivo with rapamycin reduced serum levels of IL-1β in response to challenge with LPS. These data demonstrate that autophagy controls the production of IL-1β through at least two separate mechanisms: by targeting pro-IL-1β for lysosomal degradation and by regulating activation of the NLRP3 inflammasome. IntroductionIL-1β is an important proinflammatory cytokine, released at sites of infection or injury, that regulates diverse physiological responses, including cellular recruitment, appetite, sleep, and body temperature (1Dinarello C.A. Eur. J. Immunol. 2010; 40: 599-606Crossref PubMed Scopus (188) Google Scholar). IL-1β is first produced as a proform in response to inflammatory stimuli, such as TLR ligands. This inactive precursor is cleaved into the bioactive (p17) molecule by caspase 1, following the activation of an inflammasome (2Schroder K. Tschopp J. Cell. 2010; 140: 821-832Abstract Full Text Full Text PDF PubMed Scopus (4001) Google Scholar). Inflammasomes are molecular scaffolds that trigger the activation of caspase 1 and subsequent maturation of IL-1β and IL-18. Typically, inflammasomes are formed from at least one member of the cytosolic innate immune sensor family, the NOD-like receptors (NLRs), including NLRP1, NLRP3, and NLRC4, coupled with the adaptor apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC or PYCARD) and caspase 1 (2Schroder K. Tschopp J. Cell. 2010; 140: 821-832Abstract Full Text Full Text PDF PubMed Scopus (4001) Google Scholar). The NLRP3 inflammasome is the best characterized to date and is activated by a number of endogenous and exogenous signals.Most studies in vitro employ TLR ligands, particularly LPS, to induce pro-IL-1β formation, but in many cases, this is not enough to stimulate inflammasome activation and secretion of the mature cytokine. Instead, a second signal is commonly required, and this can come from a number of endogenous and exogenous sources, including ATP and particulates, including uric acid crystals, amyloid-β, silica, asbestos, synthetic microparticles, and alum (3Eisenbarth S.C. Colegio O.R. O'Connor W. Sutterwala F.S. Flavell R.A. Nature. 2008; 453: 1122-1126Crossref PubMed Scopus (1176) Google Scholar, 4Hornung V. Bauernfeind F. Halle A. Samstad E.O. Kono H. Rock K.L. Fitzgerald K.A. Latz E. Nat. Immunol. 2008; 9: 847-856Crossref PubMed Scopus (2110) Google Scholar, 5Li H. Nookala S. Re F. J. Immunol. 2007; 178: 5271-5276Crossref PubMed Scopus (258) Google Scholar, 6Martinon F. Pétrilli V. Mayor A. Tardivel A. Tschopp J. Nature. 2006; 440: 237-241Crossref PubMed Scopus (3685) Google Scholar, 7Masters S.L. Dunne A. Subramanian S.L. Hull R.L. Tannahill G.M. Sharp F.A. Becker C. Franchi L. Yoshihara E. Chen Z. Mullooly N. Mielke L.A. Harris J. Coll R.C. Mills K.H. Mok K.H. Newsholme P. Nuñez G. Yodoi J. Kahn S.E. Lavelle E.C. O'Neill L.A. Nat. Immunol. 2010; 11: 897-904Crossref PubMed Scopus (949) Google Scholar, 8Sharp F.A. Ruane D. Claass B. Creagh E. Harris J. Malyala P. Singh M. O'Hagan D.T. Pétrilli V. Tschopp J. O'Neill L.A. Lavelle E.C. Proc. Natl. Acad. Sci. U.S.A. 2009; 106: 870-875Crossref PubMed Scopus (427) Google Scholar). Extracellular ATP triggers the P2X7 ATP-gated ion channel, leading to K+ efflux and induces recruitment of the pannexin-1 membrane pore (9Kanneganti T.D. Lamkanfi M. Kim Y.G. Chen G. Park J.H. Franchi L. Vandenabeele P. Núñez G. Immunity. 2007; 26: 433-443Abstract Full Text Full Text PDF PubMed Scopus (439) Google Scholar). This may then allow extracellular NLRP3 agonists to enter the cell and activate inflammasome assembly (9Kanneganti T.D. Lamkanfi M. Kim Y.G. Chen G. Park J.H. Franchi L. Vandenabeele P. Núñez G. Immunity. 2007; 26: 433-443Abstract Full Text Full Text PDF PubMed Scopus (439) Google Scholar). Particulates have been proposed to act through one of two mechanisms. Uptake of particulates by phagocytes may lead to lysosomal damage and release of lysosomal products into the cytosol, which activates NLRP3 (4Hornung V. Bauernfeind F. Halle A. Samstad E.O. Kono H. Rock K.L. Fitzgerald K.A. Latz E. Nat. Immunol. 2008; 9: 847-856Crossref PubMed Scopus (2110) Google Scholar, 10Halle A. Hornung V. Petzold G.C. Stewart C.R. Monks B.G. Reinheckel T. Fitzgerald K.A. Latz E. Moore K.J. Golenbock D.T. Nat. Immunol. 2008; 9: 857-865Crossref PubMed Scopus (1716) Google Scholar). In particular, the lysosomal protease cathepsin B has been implicated, due to the inhibitory effects of the cathepsin B inhibitor CA-074 methyl ester on IL-1β secretion (4Hornung V. Bauernfeind F. Halle A. Samstad E.O. Kono H. Rock K.L. Fitzgerald K.A. Latz E. Nat. Immunol. 2008; 9: 847-856Crossref PubMed Scopus (2110) Google Scholar, 8Sharp F.A. Ruane D. Claass B. Creagh E. Harris J. Malyala P. Singh M. O'Hagan D.T. Pétrilli V. Tschopp J. O'Neill L.A. Lavelle E.C. Proc. Natl. Acad. Sci. U.S.A. 2009; 106: 870-875Crossref PubMed Scopus (427) Google Scholar, 10Halle A. Hornung V. Petzold G.C. Stewart C.R. Monks B.G. Reinheckel T. Fitzgerald K.A. Latz E. Moore K.J. Golenbock D.T. Nat. Immunol. 2008; 9: 857-865Crossref PubMed Scopus (1716) Google Scholar). Alternatively, others have proposed that NLRP3 agonists induce inflammasome assembly by stimulating the production of reactive oxygen species (ROS) 5The abbreviations used are: ROS, reactive oxygen species; iBMM, immortalized bone marrow-derived macrophage(s); TLR, Toll-like receptor; BMDC, bone marrow-derived dendritic cell(s); PI, propidium iodide; ANOVA, analysis of variance; 3-MA, 3-methyladenine. (11Cruz C.M. Rinna A. Forman H.J. Ventura A.L. Persechini P.M. Ojcius D.M. J. Biol. Chem. 2007; 282: 2871-2879Abstract Full Text Full Text PDF PubMed Scopus (573) Google Scholar, 12Dostert C. Pétrilli V. Van Bruggen R. Steele C. Mossman B.T. Tschopp J. Science. 2008; 320: 674-677Crossref PubMed Scopus (1979) Google Scholar, 13Pétrilli V. Papin S. Dostert C. Mayor A. Martinon F. Tschopp J. Cell Death Differ. 2007; 14: 1583-1589Crossref PubMed Scopus (1053) Google Scholar).Autophagy is a highly conserved homeostatic process for the sequestration and degradation of cytosolic macromolecules, excess, or damaged organelles and some pathogens (14Deretic V. Curr. Opin. Cell Biol. 2010; 22: 252-262Crossref PubMed Scopus (157) Google Scholar, 15Monastyrska I. Klionsky D.J. Mol. Aspects Med. 2006; 27: 483-494Crossref PubMed Scopus (81) Google Scholar, 16Moreau K. Luo S. Rubinsztein D.C. Curr. Opin. Cell Biol. 2010; 22: 206-211Crossref PubMed Scopus (210) Google Scholar). Controlled by the products of autophagy-related genes (Atg), autophagy occurs under normal physiological conditions but can be up-regulated by numerous factors, including nutrient deprivation and pharmacological inhibitors of the mammalian target of rapamycin (mTOR). In addition, autophagy is regulated by cytokines; it is up-regulated by IFN-γ and TNF-α (17Gutierrez M.G. Master S.S. Singh S.B. Taylor G.A. Colombo M.I. Deretic V. Cell. 2004; 119: 753-766Abstract Full Text Full Text PDF PubMed Scopus (1734) Google Scholar, 18Harris J. Keane J. Clin. Exp. Immunol. 2010; 161: 1-9PubMed Google Scholar) and inhibited by IL-4 and IL-13 (19Harris J. De Haro S.A. Master S.S. Keane J. Roberts E.A. Delgado M. Deretic V. Immunity. 2007; 27: 505-517Abstract Full Text Full Text PDF PubMed Scopus (362) Google Scholar). It was previously reported that inhibition of autophagy in macrophages by knockdown of Atg7 or Atg16L1 promoted the secretion of IL-1β in response to LPS (20Saitoh T. Fujita N. Jang M.H. Uematsu S. Yang B.G. Satoh T. Omori H. Noda T. Yamamoto N. Komatsu M. Tanaka K. Kawai T. Tsujimura T. Takeuchi O. Yoshimori T. Akira S. Nature. 2008; 456: 264-268Crossref PubMed Scopus (1595) Google Scholar). The mechanisms behind this observation, or the inflammasome responsible, have not been fully determined, although the process was found to be dependent on signaling via TIR (Toll/IL-1 receptor) domain-containing adaptor inducing IFN-β (TRIF) and ROS (20Saitoh T. Fujita N. Jang M.H. Uematsu S. Yang B.G. Satoh T. Omori H. Noda T. Yamamoto N. Komatsu M. Tanaka K. Kawai T. Tsujimura T. Takeuchi O. Yoshimori T. Akira S. Nature. 2008; 456: 264-268Crossref PubMed Scopus (1595) Google Scholar).The aim of this study was to determine the mechanisms behind autophagy-dependent regulation of IL-1β secretion. Using bone marrow-derived macrophages (iBMM) and DC (BMDC) from knock-out mice we found that autophagy regulates the NLRP3 inflammasome. Moreover, we found that after TLR ligation in macrophages IL-1β was specifically sequestered into autophagosomes. Furthermore, induction of autophagy using rapamycin resulted in the loss of intracellular pro-IL-1β and inhibited secretion of mature IL-1β in cells stimulated with LPS and alum, chitosan or ATP and reduced IL-1β in the blood of mice challenged with LPS.DISCUSSIONThe link between autophagy and innate and adaptive immunity is now well established. In particular, autophagy has been demonstrated to play a role in the maturation of pathogen-containing phagosomes and MHC class II presentation of viral antigens (17Gutierrez M.G. Master S.S. Singh S.B. Taylor G.A. Colombo M.I. Deretic V. Cell. 2004; 119: 753-766Abstract Full Text Full Text PDF PubMed Scopus (1734) Google Scholar, 30Paludan C. Schmid D. Landthaler M. Vockerodt M. Kube D. Tuschl T. Münz C. Science. 2005; 307: 593-596Crossref PubMed Scopus (701) Google Scholar). Moreover, autophagy is itself regulated by cytokines and may be an effector of Th1/Th2 polarization; it is induced by IFN-γ and TNF-α (17Gutierrez M.G. Master S.S. Singh S.B. Taylor G.A. Colombo M.I. Deretic V. Cell. 2004; 119: 753-766Abstract Full Text Full Text PDF PubMed Scopus (1734) Google Scholar, 18Harris J. Keane J. Clin. Exp. Immunol. 2010; 161: 1-9PubMed Google Scholar) and inhibited by IL-4 and IL-13 (19Harris J. De Haro S.A. Master S.S. Keane J. Roberts E.A. Delgado M. Deretic V. Immunity. 2007; 27: 505-517Abstract Full Text Full Text PDF PubMed Scopus (362) Google Scholar). In addition, inflammatory stimuli, including LPS and other TLR agonists, have been shown to induce autophagy (31Delgado M.A. Elmaoued R.A. Davis A.S. Kyei G. Deretic V. EMBO J. 2008; 27: 1110-1121Crossref PubMed Scopus (604) Google Scholar, 32Shi C.S. Kehrl J.H. J. Biol. Chem. 2008; 283: 33175-33182Abstract Full Text Full Text PDF PubMed Scopus (312) Google Scholar, 33Xu Y. Jagannath C. Liu X.D. Sharafkhaneh A. Kolodziejska K.E. Eissa N.T. Immunity. 2007; 27: 135-144Abstract Full Text Full Text PDF PubMed Scopus (718) Google Scholar). A recent study has suggested that autophagy may also be a regulator of inflammation, modulating inflammasome activation and release of IL-1β (20Saitoh T. Fujita N. Jang M.H. Uematsu S. Yang B.G. Satoh T. Omori H. Noda T. Yamamoto N. Komatsu M. Tanaka K. Kawai T. Tsujimura T. Takeuchi O. Yoshimori T. Akira S. Nature. 2008; 456: 264-268Crossref PubMed Scopus (1595) Google Scholar). Here, we show that the inhibition of autophagy in LPS-activated BMDC and iBMM leads to activation of the NLRP3 inflammasome and secretion of IL-1β and IL-18. This is dependent on caspase 1, ASC, and TRIF and may involve the generation of ROS.Although it is clear from this study and that of Saitoh et al. (20Saitoh T. Fujita N. Jang M.H. Uematsu S. Yang B.G. Satoh T. Omori H. Noda T. Yamamoto N. Komatsu M. Tanaka K. Kawai T. Tsujimura T. Takeuchi O. Yoshimori T. Akira S. Nature. 2008; 456: 264-268Crossref PubMed Scopus (1595) Google Scholar) that activation of the inflammasome by LPS in the absence of autophagy is dependent on TRIF signaling, the mechanism behind this is not clear. Both TRIF and MyD88 can mediate TLR-induced production of pro-IL-1β and activation of the NLRP3 inflammasome, as demonstrated by the fact that all the TLR agonists we tested can induce production of pro-IL-1β and secretion of mature IL-1β, when given in combination with ATP. Moreover, our data show that although both TRIF−/− and MyD88−/− BMDC show equally reduced secretion of IL-1β in response to LPS with ATP or LPS with alum, compared with WT cells, both still secrete significantly more IL-1β than cells treated with LPS alone. This suggests that, in the case of LPS, one can compensate for the other, at least to a degree, but the full response is dependent on both pathways. Indeed, BMDC from TRIF−/− MyD88−/− double knock-out mice do not respond at all to LPS with ATP or alum (data not shown). However, the response of BMDC to LPS with 3-MA is completely abrogated in TRIF−/− cells but is still present in MyD88−/− cells. This would suggest that, unlike LPS with ATP or alum, the role of TRIF in response to LPS and 3-MA cannot be compensated for by the presence of MyD88. Interestingly, TLR agonists can induce autophagy in macrophages through both TRIF- and MyD88-dependent pathways (31Delgado M.A. Elmaoued R.A. Davis A.S. Kyei G. Deretic V. EMBO J. 2008; 27: 1110-1121Crossref PubMed Scopus (604) Google Scholar, 32Shi C.S. Kehrl J.H. J. Biol. Chem. 2008; 283: 33175-33182Abstract Full Text Full Text PDF PubMed Scopus (312) Google Scholar, 33Xu Y. Jagannath C. Liu X.D. Sharafkhaneh A. Kolodziejska K.E. Eissa N.T. Immunity. 2007; 27: 135-144Abstract Full Text Full Text PDF PubMed Scopus (718) Google Scholar), although we have found that LPS-induced autophagy in BMDM requires MyD88, but not TRIF, signaling. 6J. Harris, A. O'Shea, and E. C. Lavelle, unpublished observations.Numerous studies have demonstrated a role for ROS, particularly peroxynitrite, in the processing and secretion of IL-1β (11Cruz C.M. Rinna A. Forman H.J. Ventura A.L. Persechini P.M. Ojcius D.M. J. Biol. Chem. 2007; 282: 2871-2879Abstract Full Text Full Text PDF PubMed Scopus (573) Google Scholar, 12Dostert C. Pétrilli V. Van Bruggen R. Steele C. Mossman B.T. Tschopp J. Science. 2008; 320: 674-677Crossref PubMed Scopus (1979) Google Scholar, 20Saitoh T. Fujita N. Jang M.H. Uematsu S. Yang B.G. Satoh T. Omori H. Noda T. Yamamoto N. Komatsu M. Tanaka K. Kawai T. Tsujimura T. Takeuchi O. Yoshimori T. Akira S. Nature. 2008; 456: 264-268Crossref PubMed Scopus (1595) Google Scholar, 34Hewinson J. Moore S.F. Glover C. Watts A.G. MacKenzie A.B. J. Immunol. 2008; 180: 8410-8420Crossref PubMed Scopus (98) Google Scholar), although other studies have suggested that ROS are not involved in IL-1β processing or may in fact dampen IL-1β-induced inflammation (35Romani L. Fallarino F. De Luca A. Montagnoli C. D'Angelo C. Zelante T. Vacca C. Bistoni F. Fioretti M.C. Grohmann U. Segal B.H. Puccetti P. Nature. 2008; 451: 211-215Crossref PubMed Scopus (445) Google Scholar, 36van de Veerdonk F.L. Smeekens S.P. Joosten L.A. Kullberg B.J. Dinarello C.A. van der Meer J.W. Netea M.G. Proc. Natl. Acad. Sci. U.S.A. 2010; 107: 3030-3033Crossref PubMed Scopus (204) Google Scholar). Saitoh et al. (20Saitoh T. Fujita N. Jang M.H. Uematsu S. Yang B.G. Satoh T. Omori H. Noda T. Yamamoto N. Komatsu M. Tanaka K. Kawai T. Tsujimura T. Takeuchi O. Yoshimori T. Akira S. Nature. 2008; 456: 264-268Crossref PubMed Scopus (1595) Google Scholar) found that Atg16L1-deficient macrophages generated higher levels of ROS in response to LPS compared with WT or Atg16L1/TRIF double-deficient cells, suggesting that autophagy is an important regulator of intracellular ROS. Although we did not see an increase in LPS-induced ROS generation in 3-MA-treated BMDC or iBMM (data not shown), we did find that the ROS scavenger NAc inhibited IL-1β secretion in response to LPS in combination with either wortmannin or 3-MA. However, we found that IL-1β secretion by iBMM deficient in the phagocytic NADPH oxidase, NOX2 (gp91phox), was not impaired in response to LPS with 3-MA or LPS with ATP or alum. This would suggest either that ROS from an alternative source are involved in activation of the NLRP3 inflammasome or that NAc inhibits inflammasome activation via a ROS-independent mechanism. One possible alternative source of ROS is from altered or damaged mitochondria and peroxisomes. Given that autophagy is involved in the removal of these organelles (15Monastyrska I. Klionsky D.J. Mol. Aspects Med. 2006; 27: 483-494Crossref PubMed Scopus (81) Google Scholar, 16Moreau K. Luo S. Rubinsztein D.C. Curr. Opin. Cell Biol. 2010; 22: 206-211Crossref PubMed Scopus (210) Google Scholar), this could represent a mechanism for the inflammasome-activating action of autophagy inhibitors. Indeed, a recent study has demonstrated that ROS from mitochondria can activate the NLRP3 inflammasome in human THP-1 cells and that autophagy of mitochondria (mitophagy) inhibits this (37Zhou R. Yazdi A.S. Menu P. Tschopp J. Nature. 2010; Google Scholar). Moreover, ROS derived from both mitochondria and NADPH oxidases stimulate autophagy (38Chen Y. Azad M.B. Gibson S.B. Cell Death Differ. 2009; 16: 1040-1052Crossref PubMed Scopus (594) Google Scholar, 39Huang J. Canadien V. Lam G.Y. Steinberg B.E. Dinauer M.C. Magalhaes M.A. Glogauer M. Grinstein S. Brumell J.H. Proc. Natl. Acad. Sci. U.S.A. 2009; 106: 6226-6231Crossref PubMed Scopus (439) Google Scholar).Various studies have demonstrated a role for potassium efflux and/or lysosomal disruption/cathepsin B in the NLRP3-dependent processing and secretion of IL-1β (4Hornung V. Bauernfeind F. Halle A. Samstad E.O. Kono H. Rock K.L. Fitzgerald K.A. Latz E. Nat. Immunol. 2008; 9: 847-856Crossref PubMed Scopus (2110) Google Scholar, 8Sharp F.A. Ruane D. Claass B. Creagh E. Harris J. Malyala P. Singh M. O'Hagan D.T. Pétrilli V. Tschopp J. O'Neill L.A. Lavelle E.C. Proc. Natl. Acad. Sci. U.S.A. 2009; 106: 870-875Crossref PubMed Scopus (427) Google Scholar, 10Halle A. Hornung V. Petzold G.C. Stewart C.R. Monks B.G. Reinheckel T. Fitzgerald K.A. Latz E. Moore K.J. Golenbock D.T. Nat. Immunol. 2008; 9: 857-865Crossref PubMed Scopus (1716) Google Scholar, 13Pétrilli V. Papin S. Dostert C. Mayor A. Martinon F. Tschopp J. Cell Death Differ. 2007; 14: 1583-1589Crossref PubMed Scopus (1053) Google Scholar). Moreover, Saitoh et al. (20Saitoh T. Fujita N. Jang M.H. Uematsu S. Yang B.G. Satoh T. Omori H. Noda T. Yamamoto N. Komatsu M. Tanaka K. Kawai T. Tsujimura T. Takeuchi O. Yoshimori T. Akira S. Nature. 2008; 456: 264-268Crossref PubMed Scopus (1595) Google Scholar) found that inhibition of potassium efflux with extracellular KCl prevented LPS-induced IL-1β secretion in macrophages deficient in Atg16L1, which is involved in the formation of autophagosomes. In agreement with this, we found that KCl inhibited LPS-induced IL-1β secretion in macrophages treated with 3-MA at high concentrations. However, at these concentrations, IL-6 production was also abrogated, which may suggest a general inhibitory or toxic effect.Our finding that IL-1β is sequestered into autophagosomes suggests a previously unidentified role for autophagy in controlling inflammatory responses in macrophages and dendritic cells. Moreover, the fact that further induction of autophagy with rapamycin in LPS-treated cells leads to the loss of intracellular pro-IL-1β and inhibition of IL-1β secretion after treatment with LPS and alum, chitosan, or ATP strongly suggests that autophagosomes specifically target pro-IL-1β for degradation. Moreover, caspase 1 was not seen in autophagosomes, suggesting that autophagosomes do not act as a platform for inflammasome assembly and processing of IL-1β, but rather segregate pro-IL-1β from caspase 1. This sequestration of IL-1β by autophagosomes might explain why inhibition of autophagy leads to increased secretion of IL-1β in response to LPS; more pro-IL-1β is available in the cytosol. However, LPS-induced inflammasome activation and secretion of IL-1β by cells deficient in autophagy is dependent on TRIF, while both MyD88- and TRIF-dependent mechanisms lead to the generation of pro-IL-1β and the sequestration of IL-1β into autophagosomes, as demonstrated by our experiments with other TLR agonists, including poly(I:C), which signals through TRIF and PAM3CysK4, R837, and CpG, which signal through MyD88 (40O'Neill L.A. Bowie A.G. Nat. Rev. Immunol. 2007; 7: 353-364Crossref PubMed Scopus (1971) Google Scholar). Thus, these data suggest that inhibition of autophagy increases IL-1β secretion through two different mechanisms. First, inhibiting autophagy prevents degradation of pro-IL-1β, leaving more of the cytokine available in the cytosol for processing and secretion. Second, inhibition of autophagy leads to activation of the NLRP3 inflammasome and caspase 1-dependent processing of IL-1β through a ROS/TRIF-dependent mechanism.Previous studies have implicated the autophagy gene Atg16L 1 as a candidate gene for susceptibility to Crohn disease (41Hampe J. Franke A. Rosenstiel P. Till A. Teuber M. Huse K. Albrecht M. Mayr G. De La Vega F.M. Briggs J. Günther S. Prescott N.J. Onnie C.M. Häsler R. Sipos B. Fölsch U.R. Lengauer T. Platzer M. Mathew C.G. Krawczak M. Schreiber S. Nat. Genet. 2007; 39: 207-211Crossref PubMed Scopus (1517) Google Scholar, 42Prescott N.J. Fisher S.A. Franke A. Hampe J. Onnie C.M. Soars D. Bagnall R. Mirza M.M. Sanderson J. Forbes A. Mansfield J.C. Lewis C.M. Schreiber S. Mathew C.G. Gastroenterology. 2007; 132: 1665-1671Abstract Full Text Full Text PDF PubMed Scopus (246) Google Scholar, 43Rioux J.D. Xavier R.J. Taylor K.D. Silverberg M.S. Goyette P. Huett A. Green T. Kuballa P. Barmada M.M. Datta L.W. Shugart Y.Y. Griffiths A.M. Targan S.R. Ippoliti A.F. Bernard E.J. Mei L. Nicolae D.L. Regueiro M. Schumm L.P. Steinhart A.H. Rotter J.I. Duerr R.H. Cho J.H. Daly M.J. Brant S.R. Nat. Genet. 2007; 39: 596-604Crossref PubMed Scopus (1458) Google Scholar), and Saitoh et al. (20Saitoh T. Fujita N. Jang M.H. Uematsu S. Yang B.G. Satoh T. Omori H. Noda T. Yamamoto N. Komatsu M. Tanaka K. Kawai T. Tsujimura T. Takeuchi O. Yoshimori T. Akira S. Nature. 2008; 456: 264-268Crossref PubMed Scopus (1595) Google Scholar) demonstrated that loss of ATG16L1 in mouse hematopoietic cells renders the animals highly susceptible to dextran sulfate sodium-induced acute colitis. Using an in vivo LPS challenge model, we have demonstrated that rapamycin, a potent activator of autophagy, reduces serum levels of IL-1β in mice, compared with those treated with LPS alone. These data indicate that autophagy has an important role to play in regulating acute inflammation in vivo. Conversely, a recent study has demonstrated that serum IL-1β and IL-18 levels in MAPLC3−/− mice are raised compared with WT in response to LPS challenge (44Nakahira K. Haspel J.A. Rathinam V.A. Lee S.J. Dolinay T. Lam H.C. Englert J.A. Rabinovitch M. Cernadas M. Kim H.P. Fitzgerald K.A. Ryter S.W. Choi A.M. Nat. Immunol. 2010; (in press)PubMed Google Scholar). Thus, short-term induction of autophagy may represent a novel therapeutic strategy for sepsis and fever, whereas targeted administration of rapamycin or alternative autophagy-inducing compounds might offer new remedies for inflammatory conditions such as Crohn disease.In summary, we have demonstrated that the inhibition of autophagy in the presence of TLR3 or TLR4 signaling leads to activation of the NLRP3 inflammasome and secretion of IL-1β and IL-18. This is dependent on caspase 1 and on signaling via the TRIF pathway. In addition, we found that inhibitors of ROS and potassium efflux inhibited IL-1β secretion in response to autophagy blockade. Stimulation of cells with LPS induces autophagy and results in IL-1β being sequestered by autophagosomes, suggesting that autophagy may control inflammation through the degradation of pro-IL-1β. Furthermore, the induction of autophagy in mice using rapamycin reduced LPS-induced elevation of serum IL-1β. Thus, we present a novel mechanism by which autophagy can regulate inflammatory responses in antigen-presenting cells. IntroductionIL-1β is an important proinflammatory cytokine, released at sites of infection or injury, that regulates diverse physiological responses, including cellular recruitment, appetite, sleep, and body temperature (1Dinarello C.A. Eur. J. Immunol. 2010; 40: 599-606Crossref PubMed Scopus (188) Google Scholar). IL-1β is first produced as a proform in response to inflammatory stimuli, such as TLR ligands. This inactive precursor is cleaved into the bioactive (p17) molecule by caspase 1, following the activation of an inflammasome (2Schroder K. Tschopp J. Cell. 2010; 140: 821-832Abstract Full Text Full Text PDF PubMed Scopus (4001) Google Scholar). Inflammasomes are molecular scaffolds that trigger the activation of caspase 1 and subsequent maturation of IL-1β and IL-18. Typically, inflammasomes are formed from at least one member of the cytosolic innate immune sensor family, the NOD-like receptors (NLRs), including NLRP1, NLRP3, and NLRC4, coupled with the adaptor apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC or PYCARD) and caspase 1 (2Schroder K. Tschopp J. Cell. 2010; 140: 821-832Abstract Full Text Full Text PDF PubMed Scopus (4001) Google Scholar). The NLRP3 inflammasome is the best characterized to date and is activated by a number of endogenous and exogenous signals.Most studies in vitro employ TLR ligands, particularly LPS, to induce pro-IL-1β formation, but in many cases, this is not enough to stimulate inflammasome activation and secretion of the mature cytokine. Instead, a second signal is commonly required, and this can come from a number of endogenous and exogenous sources, including ATP and particulates, including uric acid crystals, amyloid-β, silica, asbestos, synthetic microparticles, and alum (3Eisenbarth S.C. Colegio O.R. O'Connor W. Sutterwala F.S. Flavell R.A. Nature. 2008; 453: 1122-1126Crossref PubMed Scopus (1176) Google Scholar, 4Hornung V. Bauernfeind F. Halle A. Samstad E.O. Kono H. Rock K.L. Fitzgerald K.A. Latz E. Nat. Immunol. 2008; 9: 847-856Crossref PubMed Scopus (2110) Google Scholar, 5Li H. Nookala S. Re F. J. Immunol. 2007; 178: 5271-5276Crossref PubMed Scopus (258) Google Scholar, 6Martinon F. Pétrilli V. Mayor A. Tardivel A. Tschopp J. Nature. 2006; 440: 237-241Crossref PubMed Scopus (3685) Google Scholar, 7Masters S.L. Dunne A. Subramanian S.L. Hull R.L. Tannahill G.M. Sharp F.A. Becker C. Franchi L. Yoshihara E. Chen Z. Mullooly N. Mielke L.A. Harris J. Coll R.C. Mills K.H. Mok K.H. Newsholme P. Nuñez G. Yodoi J. Kahn S.E. Lavelle E.C. O'Neill L.A. Nat. Immunol. 2010; 11: 897-904Crossref PubMed Scopus (949) Google Scholar, 8Sharp F.A. Ruane D. Claass B. Creagh E. Harris J. Malyala P. Singh M. O'Hagan D.T. Pétrilli V. Tschopp J. O'Neill L.A. Lavelle E.C. Proc. Natl. Acad. Sci. U.S.A. 2009; 106: 870-875Crossref PubMed Scopus (427) Google Scholar). Extracellular ATP triggers the P2X7 ATP-gated ion channel, leading to K+ efflux and induces recruitment of the pannexin-1 membrane pore (9Kanneganti T.D. Lamkanfi M. Kim Y.G. Chen G. Park J.H. Franchi L. Vandenabeele P. Núñez G. Immunity. 2007; 26: 433-443Abstract Full Text Full Text PDF PubMed Scopus (439) Google Scholar). This may then allow extracellular NLRP3 agonists to enter the cell and activate inflammasome assembly (9Kanneganti T.D. Lamkanfi M. Kim Y.G. Chen G. Park J.H. Franchi L. Vandenabeele P. Núñez G. Immunity. 2007; 26: 433-443Abstract Full Text Full Text PDF PubMed Scopus (439) Google Scholar). Particulates have been proposed to act through one of two mechanisms. Uptake of particulates by phagocytes may lead to lysosomal damage and release of lysosomal products into the cytosol, which activates NLRP3 (4Hornung V. Bauernfeind F. Halle A. Samstad E.O. Kono H. Rock K.L. Fitzgerald K.A. Latz E. Nat. Immunol. 2008; 9: 847-856Crossref PubMed Scopus (2110) Google Scholar, 10Halle A. Hornung V. Petzold G.C. Stewart C.R. Monks B.G. Reinheckel T. Fitzgerald K.A. Latz E. Moore K.J. Golenbock D.T. Nat. Immunol. 2008; 9: 857-865Crossref PubMed Scopus (1716) Google Scholar). In particular, the lysosomal protease cathepsin B has been implicated, due to the inhibitory effects of the cathepsin B inhibitor CA-074 methyl ester on IL-1β" @default.
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