Inflammasome-independent role of the apoptosis-associated speck-like protein containing CARD (ASC) in the adjuvant effect of MF59

Ellebedy, Ali H.; Lupfer, Christopher R.; Ghoneim, Hazem E.; DeBeauchamp, Jennifer; Kanneganti, Thirumala‐Devi; Webby, Richard J.

doi:10.1073/pnas.1012455108

Cited by 105 publications

(90 citation statements)

References 30 publications

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“…These data are in agreement with some recent reports on alum adjuvanticity and suggest that adjuvants based on oil emulsions are also independent of inflammasome activation (13,14). In addition, our data are consistent with a recent study showing that MF59 adjuvanticity to a H5 influenza vaccine is independent of Nlrp3 and caspase 1, but depends on the adaptor protein ASC (25). We cannot exclude that other inflammasome complexes may play a redundant role with Nlrp3 in vivo after the injection of emulsions (26).…”

Section: Discussionsupporting

confidence: 93%

Adjuvanticity of the oil-in-water emulsion MF59 is independent of Nlrp3 inflammasome but requires the adaptor protein MyD88

Seubert

Calabrό

Santini

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

160

127

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Oil-in-water emulsions have been successfully used to increase the efficacy, immunogenicity, and cross-protection of human vaccines; however, their mechanism of action is still largely unknown. Nlrp3 inflammasome has been previously associated to the activity of alum, another adjuvant broadly used in human vaccines, and MyD88 adaptor protein is required for the adjuvanticity of most Toll-like receptor agonists. We compared the contribution of Nlrp3 and MyD88 to the adjuvanticity of alum, the oil-in-water emulsion MF59, and complete Freund's adjuvant in mice using a threecomponent vaccine against serogroup B Neisseria meningitidis (rMenB). Although the basal antibody responses to the nonadjuvanted rMenB vaccine were largely dependent on Nlrp3, the highlevel antibody responses induced by alum, MF59, or complete Freund's adjuvant did not require Nlrp3. Surprisingly, we found that MF59 requires MyD88 to enhance bactericidal antibody responses to the rMenB vaccine. Because MF59 did not activate any of the Tolllike receptors in vitro, we propose that MF59 requires MyD88 for a Toll-like receptor-independent signaling pathway.

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Section: Discussionsupporting

confidence: 93%

Adjuvanticity of the oil-in-water emulsion MF59 is independent of Nlrp3 inflammasome but requires the adaptor protein MyD88

Seubert

Calabrό

Santini

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

160

127

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“…Consistent with findings with NLRP3 inflammasome (23,48), AIM2 deficiency seems to be dispensable for regulating the adaptive immune response in influenza infection. AIM2-deficient mice display similar levels of influenza-specific IgG and similar amounts of CD4 + and CD8 + T cell influx into the lung (Supplemental Fig.…”

Section: Ams Are the Likely Target Cells For Aim2 Function In Regulatsupporting

confidence: 86%

AIM2 Inflammasome Is Critical for Influenza-Induced Lung Injury and Mortality

Luo

Alcorn

Chen

et al. 2017

The Journal of Immunology

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The absent in melanoma 2 (AIM2) inflammasome plays an important role in many viral and bacterial infections, but very little is known about its role in RNA virus infection, including influenza A virus (IAV). In this study, we have designed in vivo and in vitro studies to determine the role of AIM2 in infections with lethal doses of IAVs A/PR8/34 and A/California/07/09. In wild-type mice, IAV infection enhanced AIM2 expression, induced dsDNA release, and stimulated caspase-1 activation and release of cleaved IL-1β in the lung, which was significantly reduced in AIM2-deficient mice. Interestingly, AIM2 deficiency did not affect the transcription of caspase-1 and IL-1β. In addition, AIM2-deficient mice exhibited attenuated lung injury and significantly improved survival against IAV challenges, but did not alter viral burden in the lung. However, AIM2 deficiency did not seem to affect adaptive immune response against IAV infections. Furthermore, experiments with AIM2-specific small interfering RNA–treated and AIM2-deficient human and mouse lung alveolar macrophages and type II cells indicated a macrophage-specific function of AIM2 in regulation of IAV-stimulated proinflammatory response. Collectively, our results demonstrate that influenza infection activates the AIM2 inflammasome, which plays a critical role in IAV-induced lung injury and mortality. AIM2 might serve as a therapeutic target for combating influenza-associated morbidity and mortality without compromising the host antiviral responses.

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“…It forms large molecular complexes, and it is involved in the intrinsic and extrinsic pathways of apoptosis (44)(45)(46) and in the inflammasome, which is a large cytosolic protein complex, where PYCARD bridges the interaction between NLRP3 and caspase 1, leading to activation of the latter (47,48). Its involvement in the extrinsic apoptosis pathway seems to be related to activation of caspase 8 (49).…”

Section: Discussionmentioning

confidence: 99%

Lysophosphatidic acid receptor 1 suppression sensitizes rheumatoid fibroblast‐like synoviocytes to tumor necrosis factor–induced apoptosis

Orosa¹,

González²,

Mera³

et al. 2012

Arthritis & Rheumatism

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Objective. To investigate the role of lysophosphatidic acid (LPA) receptors in the proliferation and apoptosis of fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA).Methods. Expression of LPA receptors 1-3 was analyzed by real-time polymerase chain reaction (PCR). LPAR1 and LPAR2 were suppressed in RA FLS by small interfering RNA (siRNA) transfection. Proliferation of RA FLS after tumor necrosis factor (TNF) and LPA stimulation was determined with a luminescent cell viability assay. Apoptosis was analyzed by quantification of nucleosome release and measurement of activated caspase 3/7. Genes involved in the apoptotic response were identified with a human apoptosis PCR array and validated with Western blot assays. The requirement of these genes for apoptosis sensitization was assessed by siRNA transfection. Secretion of mediators of inflammation was analyzed by enzyme-linked immunosorbent assay.Results. Only LPAR1 and LPAR2 were expressed by RA FLS, and their levels were higher than those in osteoarthritis (OA) FLS. Suppression of LPAR1 abrogated TNF-induced proliferation and sensitized the RA FLS, but not the OA FLS, to TNF-induced apoptosis. These changes occurred despite an increased early inflammatory response to TNF. Sensitization to apoptosis was associated with changes in expression of multiple apoptosis-related genes. Three of the up-regulated proapoptotic genes were further studied to confirm their involvement. In contrast, suppression of LPAR2 showed no effect in any of these analyses.Conclusion. LPA 1 is an important receptor in RA FLS. Its suppression is accompanied by a global increase in the response to TNF that is ultimately dominated by sensitization to apoptosis.

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Inflammasome-independent role of the apoptosis-associated speck-like protein containing CARD (ASC) in the adjuvant effect of MF59

Cited by 105 publications

References 30 publications

Adjuvanticity of the oil-in-water emulsion MF59 is independent of Nlrp3 inflammasome but requires the adaptor protein MyD88

Adjuvanticity of the oil-in-water emulsion MF59 is independent of Nlrp3 inflammasome but requires the adaptor protein MyD88

AIM2 Inflammasome Is Critical for Influenza-Induced Lung Injury and Mortality

Lysophosphatidic acid receptor 1 suppression sensitizes rheumatoid fibroblast‐like synoviocytes to tumor necrosis factor–induced apoptosis

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