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.

Michela Terlizzi,Chantal Donovan,Chiara Colarusso,Pasquale Imitazione,Antonio Molino,Rosalinda Sorrentino,Pasquale Somma,Philip M Hansbro,Aldo Pinto,Rita P Aquino

doi:10.3389/fimmu.2018.00670

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.

Highlights

Idiopathic pulmonary fibrosis (IPF), a severe form of interstitial disease, is a chronic and irreversible respiratory disease characterized by inflammation and fibrosis [1, 2]
We found that the activation of absent in melanoma 2 (AIM2) inflammasome in IPF peripheral blood mononuclear cells (PBMCs) led to IL-1α, but not IL-1β, and TGF-β release in a TLR4-/caspase-1-/caspase-8-/calpain-independent manner, concomitantly to caspase-4 extracellular release
We found that the levels of NLRP3 were lower in IPF-derived PBMCs, explaining why its activation via LPS + ATP was not responsible for both IL-18 and IL-1α release

Summary

Introduction

Idiopathic pulmonary fibrosis (IPF), a severe form of interstitial disease, is a chronic and irreversible respiratory disease characterized by inflammation and fibrosis [1, 2]. Dysfunction in the process of tissue repairing of epithelial cells [4], fibroblast activation, and differentiation into myofibroblasts [5] with the ensuing extensive extracellular matrix deposition, are key processes involved in the fibrotic process [4, 5] In this context, postulated, the role of chronic inflammation still remains elusive. Repeated danger stimuli (i.e., silica, asbestos) trigger chronic inflammatory patterns that lead to progressive decline of pulmonary function and architecture [2] In this context, because danger stimuli are well-known activator of Nod-like receptors (NLR) which are involved in the inflammasome activation, the goal of this study was to evaluate the involvement of this latter complex. Alternative, non-canonical inflammasomes have been described, which engage caspase-8 or caspase-11 ( known as caspase-4 in humans) [9, 10], which in turn induce inflammasome-dependent caspase-1 activation and inflammasome independent, pyroptosislike cell death, via the release of such “alarmins” as IL-1α [9]

Objectives

Methods

Results

Conclusion