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

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.

DROSHA-Dependent miRNA and AIM2 Inflammasome Activation in Idiopathic Pulmonary Fibrosis

“…Terlizzi et al demonstrated that the activation of the AIM2 inflammasome is increased in peripheral blood mononuclear cells (PBMCs) from patients with IPF. The AIM2 inflammasome activation contributes to the production and release of pro-fibrotic mediators [78]. Recently, our findings demonstrated that the expression and activation of AIM2 inflammasome expression and activation is enhanced in a lung fibrosis exacerbation model [79].…”

Identification of a novel subpopulation of Caspase-4 positive Non-Small Cell Lung Cancer patients.

“…4D), implying that not only K-Ras mutation, but also p53 genetic alteration could be implied in caspase-11related pro-tumor activity in mice. Caspase-11 was described as involved in the non-canonical in ammasome pathway and associated to IL-1-like cytokines release (10,11,13,17,20). We found that IL-1β was reduced in the BAL of caspase-11 ko mice at longer time point (16 weeks) ( Fig.…”

Identification of a novel subpopulation of Caspase-4 positive Non-Small Cell Lung Cancer patients.

“…Noteworthy, the precursor form of caspase-11 was higher expressed in these latter mice compared to NMU-injected C57Bl/6, control (Ctr) mice ( Figure 4D), implying that not only K-Ras mutation, but also p53 genetic alteration could be implied in caspase-11-related pro-tumor activity in mice. Caspase-11 was described as involved in the non-canonical in ammasome pathway and associated to IL-1-like cytokine release (10,11,13,17,20). We found that IL-1β was reduced in the BAL of caspase-11 ko mice at longer time point (16 weeks) ( Figure 4E) compared to wild type mice.…”