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

• Published in: Frontiers in immunology Vol. 9; p. 670
• Main Authors: Terlizzi, Michela, Molino, Antonio, Colarusso, Chiara, Donovan, Chantal, Imitazione, Pasquale, Somma, Pasquale, Aquino, Rita P., Hansbro, Philip M., Pinto, Aldo, Sorrentino, Rosalinda
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 05.04.2018
• Subjects: absent in melanoma 2 inflammasome; caspase-4; idiopathic pulmonary fibrosis; IL-18; IL-1α; Immunology; absent in melanoma 2 inflammasome; idiopathic pulmonary fibrosis; IL-1α; IL-18; caspase-4
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2018.00670

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.