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Activation of the Absent in Melanoma 2 Inflammasome in Peripheral Blood Mononuclear Cells From Idiopathic Pulmonary Fibrosis Patients Leads to the Release of Pro-Fibrotic Mediators.
Front Immunol 2018; 9:670FI

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic fibro-proliferative disease characterized by poor prognosis, with a mean survival of ~2-3 years after definite diagnosis. The cause of IPF is still unknown but it is a heterogeneous condition in which the aberrant deposition of extracellular matrix leads to extensive lung remodeling. This remodeling is a consequence of inflammatory responses, but the mechanisms involved are poorly understood. In this study, we first analyzed a bleomycin-induced mouse model, which showed that higher expression of IL-1β, but not IL-18, was correlated to pulmonary cell infiltration and fibrosis. Then, we found that peripheral blood mononuclear cells (PBMCs) from IPF patients released IL-1α and IL-18 in a NLRP3- and calpain-independent manner after LPS ± ATP stimulation. Instead, the activation of the absent in melanoma 2 (AIM2) inflammasome induced the release of IL-1α in a caspase-1-/caspase-8-independent manner; whereas IL-18 release was caspase-1 dependent. These effects correlated with the release of the pro-fibrotic TGF-β, which was induced by AIM2 activation in a caspase-1- and TLR4-independent manner, but dependent on IL-1α. In this context, the activation of AIM2 induced the release of caspase-4 from IPF-derived PBMCs, which correlated with the mRNA levels of this caspase that was higher in IPF than in healthy PBMCs. In conclusion, our findings identify a novel molecular mechanism whereby the activation of AIM2 could lead to the activation of the non-canonical inflammasome (caspase-4 dependent) that induces the release of IL-1α responsible for the release of TGF-β from PBMCs of IPF patients.

Authors+Show Affiliations

Department of Pharmacy, University of Salerno, Fisciano, Salerno, Italy. ImmunePharma s.r.l., University of Salerno, Fisciano, Salerno, Italy.Respiratory Division, Department of Respiratory Medicine, University of Naples Federico II, Naples, Italy.Department of Pharmacy, University of Salerno, Fisciano, Salerno, Italy. ImmunePharma s.r.l., University of Salerno, Fisciano, Salerno, Italy. PhD Program in Drug Discovery and Development, Department of Pharmacy, University of Salerno, Fisciano, Italy.Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, University of Newcastle, Newcastle, NSW, Australia.Respiratory Division, Department of Respiratory Medicine, University of Naples Federico II, Naples, Italy.Department of Anatomy and Pathology, Ospedale dei Colli "Monaldi-CTO", Naples, Italy.Department of Pharmacy, University of Salerno, Fisciano, Salerno, Italy. ImmunePharma s.r.l., University of Salerno, Fisciano, Salerno, Italy.Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, University of Newcastle, Newcastle, NSW, Australia.Department of Pharmacy, University of Salerno, Fisciano, Salerno, Italy. ImmunePharma s.r.l., University of Salerno, Fisciano, Salerno, Italy.Department of Pharmacy, University of Salerno, Fisciano, Salerno, Italy. ImmunePharma s.r.l., University of Salerno, Fisciano, Salerno, Italy.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29675024

Citation

Terlizzi, Michela, et al. "Activation of the Absent in Melanoma 2 Inflammasome in Peripheral Blood Mononuclear Cells From Idiopathic Pulmonary Fibrosis Patients Leads to the Release of Pro-Fibrotic Mediators." Frontiers in Immunology, vol. 9, 2018, p. 670.
Terlizzi M, Molino A, Colarusso C, et al. Activation of the Absent in Melanoma 2 Inflammasome in Peripheral Blood Mononuclear Cells From Idiopathic Pulmonary Fibrosis Patients Leads to the Release of Pro-Fibrotic Mediators. Front Immunol. 2018;9:670.
Terlizzi, M., Molino, A., Colarusso, C., Donovan, C., Imitazione, P., Somma, P., ... Sorrentino, R. (2018). Activation of the Absent in Melanoma 2 Inflammasome in Peripheral Blood Mononuclear Cells From Idiopathic Pulmonary Fibrosis Patients Leads to the Release of Pro-Fibrotic Mediators. Frontiers in Immunology, 9, p. 670. doi:10.3389/fimmu.2018.00670.
Terlizzi M, et al. Activation of the Absent in Melanoma 2 Inflammasome in Peripheral Blood Mononuclear Cells From Idiopathic Pulmonary Fibrosis Patients Leads to the Release of Pro-Fibrotic Mediators. Front Immunol. 2018;9:670. PubMed PMID: 29675024.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Activation of the Absent in Melanoma 2 Inflammasome in Peripheral Blood Mononuclear Cells From Idiopathic Pulmonary Fibrosis Patients Leads to the Release of Pro-Fibrotic Mediators. AU - Terlizzi,Michela, AU - Molino,Antonio, AU - Colarusso,Chiara, AU - Donovan,Chantal, AU - Imitazione,Pasquale, AU - Somma,Pasquale, AU - Aquino,Rita P, AU - Hansbro,Philip M, AU - Pinto,Aldo, AU - Sorrentino,Rosalinda, Y1 - 2018/04/05/ PY - 2017/12/09/received PY - 2018/03/19/accepted PY - 2018/4/21/entrez PY - 2018/4/21/pubmed PY - 2018/4/21/medline KW - IL-18 KW - IL-1α KW - absent in melanoma 2 inflammasome KW - caspase-4 KW - idiopathic pulmonary fibrosis SP - 670 EP - 670 JF - Frontiers in immunology JO - Front Immunol VL - 9 N2 - Idiopathic pulmonary fibrosis (IPF) is a chronic fibro-proliferative disease characterized by poor prognosis, with a mean survival of ~2-3 years after definite diagnosis. The cause of IPF is still unknown but it is a heterogeneous condition in which the aberrant deposition of extracellular matrix leads to extensive lung remodeling. This remodeling is a consequence of inflammatory responses, but the mechanisms involved are poorly understood. In this study, we first analyzed a bleomycin-induced mouse model, which showed that higher expression of IL-1β, but not IL-18, was correlated to pulmonary cell infiltration and fibrosis. Then, we found that peripheral blood mononuclear cells (PBMCs) from IPF patients released IL-1α and IL-18 in a NLRP3- and calpain-independent manner after LPS ± ATP stimulation. Instead, the activation of the absent in melanoma 2 (AIM2) inflammasome induced the release of IL-1α in a caspase-1-/caspase-8-independent manner; whereas IL-18 release was caspase-1 dependent. These effects correlated with the release of the pro-fibrotic TGF-β, which was induced by AIM2 activation in a caspase-1- and TLR4-independent manner, but dependent on IL-1α. In this context, the activation of AIM2 induced the release of caspase-4 from IPF-derived PBMCs, which correlated with the mRNA levels of this caspase that was higher in IPF than in healthy PBMCs. In conclusion, our findings identify a novel molecular mechanism whereby the activation of AIM2 could lead to the activation of the non-canonical inflammasome (caspase-4 dependent) that induces the release of IL-1α responsible for the release of TGF-β from PBMCs of IPF patients. SN - 1664-3224 UR - https://www.unboundmedicine.com/medline/citation/29675024/Activation_of_the_Absent_in_Melanoma_2_Inflammasome_in_Peripheral_Blood_Mononuclear_Cells_From_Idiopathic_Pulmonary_Fibrosis_Patients_Leads_to_the_Release_of_Pro_Fibrotic_Mediators_ L2 - https://dx.doi.org/10.3389/fimmu.2018.00670 DB - PRIME DP - Unbound Medicine ER -