DROSHA-Dependent AIM2 Inflammasome Activation Contributes to Lung Inflammation during Idiopathic Pulmonary Fibrosis.

Soo Jung Cho,Ji Hun Jeong,Kyoung Sook Hong,Mihye Lee,Heather W Stout-Delgado,Jong-Seok Moon,Augustine M K Choi

doi:10.3390/cells8080938

Abstract

Idiopathic pulmonary fibrosis (IPF) has been linked to chronic lung inflammation. Drosha ribonuclease III (DROSHA), a class 2 ribonuclease III enzyme, plays a key role in microRNA (miRNA) biogenesis. However, the mechanisms by which DROSHA affects the lung inflammation during idiopathic pulmonary fibrosis (IPF) remain unclear. Here, we demonstrate that DROSHA regulates the absent in melanoma 2 (AIM2) inflammasome activation during idiopathic pulmonary fibrosis (IPF). Both DROSHA and AIM2 protein expression were elevated in alveolar macrophages of patients with IPF. We also found that DROSHA and AIM2 protein expression were increased in alveolar macrophages of lung tissues in a mouse model of bleomycin-induced pulmonary fibrosis. DROSHA deficiency suppressed AIM2 inflammasome-dependent caspase-1 activation and interleukin (IL)-1β and IL-18 secretion in primary mouse alveolar macrophages and bone marrow-derived macrophages (BMDMs). Transduction of microRNA (miRNA) increased the formation of the adaptor apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) specks, which is required for AIM2 inflammasome activation in BMDMs. Our results suggest that DROSHA promotes AIM2 inflammasome activation-dependent lung inflammation during IPF.

Highlights

Pulmonary fibrotic disorders include idiopathic pulmonary fibrosis (IPF), hypersensitivity pneumonitis, sarcoidosis, radiation-induced fibrosis, and the interstitial fibrosis associated with collagen vascular diseases such as rheumatoid arthritis and systemic lupus erythematous [1]
Immunohistochemistry staining revealed the Drosha ribonuclease III (DROSHA) protein expression was significantly elevated in alveolar macrophages of patients with IPF (IPF) compared to non-IPF patients (Control) (Figure 1B)
Since DROSHA and absent in melanoma 2 (AIM2) expression levels were elevated in alveolar macrophages during lung fibrosis, we investigated the function of DROSHA during AIM2 inflammasome activation in alveolar macrophages

Summary

Introduction

Pulmonary fibrotic disorders include idiopathic pulmonary fibrosis (IPF), hypersensitivity pneumonitis, sarcoidosis, radiation-induced fibrosis, and the interstitial fibrosis associated with collagen vascular diseases such as rheumatoid arthritis and systemic lupus erythematous [1]. IPF is the most common of these interstitial lung diseases and has an incidence in northern America estimated at between 6 and 18 per 100,000 individuals [2]. It is characterized by focal areas of chronic inflammation, aberrant immune response, epithelial cell injury, proliferation of mesenchymal cells, and dysregulated wound healing, leading to progressive respiratory failure and death [3,4]. Inflammasomes consist of sensor proteins, such as nucleotide oligomerization domain (NOD)-, leucine-rich repeat (LRR)- and pyrin domain-containing 1 (NLRP1), NLRP3, and NLRC4, or pyrin and HIN domain-containing protein (PYHIN), family members absent in melanoma 2

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