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Cross-talk between IL-6 trans-signaling and AIM2 inflammasome/IL-1ß axes bridge innate immunity and epithelial apoptosis to promote emphysema.
Ruwanpura, Saleela M; McLeod, Louise; Dousha, Lovisa F; Seow, Huei J; West, Alison C; West, Alice J; Weng, Teresa; Alanazi, Mohammad; MacDonald, Martin; King, Paul T; Bardin, Philip G; Gabay, Cem; Klinman, Dennis M; Bozinovski, Steven; Vlahos, Ross; Anderson, Gary P; Rose-John, Stefan; Saad, Mohamed I; Jenkins, Brendan J.
Afiliación
  • Ruwanpura SM; Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC 3168, Australia.
  • McLeod L; Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC 3800, Australia.
  • Dousha LF; Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC 3168, Australia.
  • Seow HJ; Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC 3800, Australia.
  • West AC; Lung Health Research Centre, Department of Biochemistry and Pharmacology, The University of Melbourne, Parkville, VIC 3050, Australia.
  • West AJ; Lung Health Research Centre, Department of Biochemistry and Pharmacology, The University of Melbourne, Parkville, VIC 3050, Australia.
  • Weng T; Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC 3168, Australia.
  • Alanazi M; Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC 3800, Australia.
  • MacDonald M; Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC 3168, Australia.
  • King PT; Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC 3800, Australia.
  • Bardin PG; Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC 3168, Australia.
  • Gabay C; Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC 3800, Australia.
  • Klinman DM; Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC 3168, Australia.
  • Bozinovski S; Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC 3800, Australia.
  • Vlahos R; Monash Lung and Sleep, Monash Health, Clayton, VIC 3168, Australia.
  • Anderson GP; Monash Lung and Sleep, Monash Health, Clayton, VIC 3168, Australia.
  • Rose-John S; Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC 3168, Australia.
  • Saad MI; Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC 3800, Australia.
  • Jenkins BJ; Monash Lung and Sleep, Monash Health, Clayton, VIC 3168, Australia.
Proc Natl Acad Sci U S A ; 119(36): e2201494119, 2022 09 06.
Article en En | MEDLINE | ID: mdl-36037355
Pulmonary emphysema is associated with dysregulated innate immune responses that promote chronic pulmonary inflammation and alveolar apoptosis, culminating in lung destruction. However, the molecular regulators of innate immunity that promote emphysema are ill-defined. Here, we investigated whether innate immune inflammasome complexes, comprising the adaptor ASC, Caspase-1 and specific pattern recognition receptors (PRRs), promote the pathogenesis of emphysema. In the lungs of emphysematous patients, as well as spontaneous gp130F/F and cigarette smoke (CS)-induced mouse models of emphysema, the expression (messenger RNA and protein) and activation of ASC, Caspase-1, and the inflammasome-associated PRR and DNA sensor AIM2 were up-regulated. AIM2 up-regulation in emphysema coincided with the biased production of the mature downstream inflammasome effector cytokine IL-1ß but not IL-18. These observations were supported by the genetic blockade of ASC, AIM2, and the IL-1 receptor and therapy with AIM2 antagonistic suppressor oligonucleotides, which ameliorated emphysema in gp130F/F mice by preventing elevated alveolar cell apoptosis. The functional requirement for AIM2 in driving apoptosis in the lung epithelium was independent of its expression in hematopoietic-derived immune cells and the recruitment of infiltrating immune cells in the lung. Genetic and inhibitor-based blockade of AIM2 also protected CS-exposed mice from pulmonary alveolar cell apoptosis. Intriguingly, IL-6 trans-signaling via the soluble IL-6 receptor, facilitated by elevated levels of IL-6, acted upstream of the AIM2 inflammasome to augment AIM2 expression in emphysema. Collectively, we reveal cross-talk between the AIM2 inflammasome/IL-1ß and IL-6 trans-signaling axes for potential exploitation as a therapeutic strategy for emphysema.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfisema Pulmonar / Interleucina-6 / Proteínas de Unión al ADN / Interleucina-1beta / Inmunidad Innata Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2022 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfisema Pulmonar / Interleucina-6 / Proteínas de Unión al ADN / Interleucina-1beta / Inmunidad Innata Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2022 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Estados Unidos