Regulatory Cues in Pulmonary Fibrosis-With Emphasis on the AIM2 Inflammasome

Abstract

Pulmonary fibrosis (PF) is a chronic lung disorder characterized by the presence of scarred and thickened lung tissues. Although the Food and Drug Administration approved two antifibrotic drugs, pirfenidone, and nintedanib, that are currently utilized for treating idiopathic PF (IPF), the clinical therapeutic efficacy remains unsatisfactory. It is crucial to develop new drugs or treatment schemes that combine pirfenidone or nintedanib to achieve more effective outcomes for PF patients. Understanding the complex mechanisms underlying PF could potentially facilitate drug discovery. Previous studies have found that the activation of inflammasomes, including nucleotide-binding and oligomerization domain (NOD)-like receptor protein (NLRP)1, NLRP3, NOD-like receptor C4, and absent in melanoma (AIM)2, contributes to lung inflammation and fibrosis. This article aims to summarize the cellular and molecular regulatory cues that contribute to PF with a particular emphasis on the role of AIM2 inflammasome in mediating pathophysiologic events during PF development. The insights gained from this research may pave the way for the development of more effective strategies for the prevention and treatment of PF.

Keywords: AIM2 inflammasome; epithelial-mesenchymal transition; inflammation; pulmonary fibrosis; senescence.

Figure 1

Pathophysiologic mechanisms underlying pulmonary fibrosis are complex and dynamic. These mechanisms include fibroblast activation, epithelial-mesenchymal transition (EMT) of alveolar epithelial cells (AECs), epithelial regeneration impairment, and imbalanced senescence, as well as dysregulation of environmental cues, including immune cell activation deficiency, deregulation of inflammation, and increasing oxidative stress.

Figure 2

AIM2 inflammasomes are classified into canonical AIM2 inflammasomes and noncanonical AIM2 inflammasomes. Canonical AIM2 inflammasomes mainly initiate caspase-1 activation by interacting with cytokine substrates (e.g., IL-1β and IL-18) to form mature cytokines, which are subsequently secreted extracellularly to induce inflammatory responses. Noncanonical AIM2 inflammasomes activate noncaspase-1 caspases (e.g., caspase-4). AIM2 activation will finally lead to pyroptotic cell death.

Figure 3

Drugs inhibiting AIM2 inflammasome activity. RDN, andrographolide, and RGFP966 can inhibit pulmonary fibrosis by impairing the activity of the AIM2 inflammasome. Rg1 and luteolin inhibit the AIM2 inflammasome in lipopolysaccharide-stimulated BV-2 cells and NSCLC xenograft mouse models, respectively. The question mark represents whether Rg1 and luteolin have the potential to treat pulmonary fibrosis is unclear.