An Allergic Lung Microenvironment Suppresses Carbon Nanotube-Induced Inflammasome Activation via STAT6-Dependent Inhibition of Caspase-1

<div><p>Background</p><p>Multi-walled carbon nanotubes (MWCNTs) represent a human health risk as mice exposed by inhalation display pulmonary fibrosis. Production of IL-1β via inflammasome activation is a mechanism of MWCNT-induced acute inflammation and has been implicated in chronic fibrogenesis. Mice sensitized to allergens have elevated T-helper 2 (Th2) cytokines, IL-4 and IL-13, and are susceptible to MWCNT-induced airway fibrosis. We postulated that Th2 cytokines would modulate MWCNT-induced inflammasome activation and IL-1β release <i>in vitro</i> and <i>in vivo</i> during allergic inflammation.</p><p>Methods</p><p>THP-1 macrophages were primed with LPS, exposed to MWCNTs and/or IL-4 or IL-13 for 24 hours, and analyzed for indicators of inflammasome activation. C57BL6 mice were sensitized to house dust mite (HDM) allergen and MWCNTs were delivered to the lungs by oropharyngeal aspiration. Mice were euthanized 1 or 21 days post-MWCNT exposure and evaluated for lung inflammasome components and allergic inflammatory responses.</p><p>Results</p><p>Priming of THP-1 macrophages with LPS increased pro-IL-1β and subsequent exposure to MWCNTs induced IL-1β secretion. IL-4 or IL-13 decreased MWCNT-induced IL-1β secretion by THP-1 cells and reduced pro-caspase-1 but not pro-IL-1β. Treatment of THP-1 cells with STAT6 inhibitors, either Leflunomide or JAK I inhibitor, blocked suppression of caspase activity by IL-4 and IL-13. <i>In vivo</i>, MWCNTs alone caused neutrophilic infiltration into the lungs of mice 1 day post-exposure and increased IL-1β in bronchoalveolar lavage fluid (BALF) and pro-caspase-1 immuno-staining in macrophages and airway epithelium. HDM sensitization alone caused eosinophilic inflammation with increased IL-13. MWCNT exposure after HDM sensitization increased total cell numbers in BALF, but decreased numbers of neutrophils and IL-1β in BALF as well as reduced pro-caspase-1 in lung tissue. Despite reduced IL-1β mice exposed to MWCNTs after HDM developed more severe airway fibrosis by 21 days and had increased pro-fibrogenic cytokine mRNAs.</p><p>Conclusions</p><p>These data indicate that Th2 cytokines suppress MWCNT-induced inflammasome activation via STAT6-dependent down-regulation of pro-caspase-1 and suggest that suppression of inflammasome activation and IL-1β by an allergic lung microenvironment is a mechanism through which MWCNTs exacerbate allergen-induced airway fibrosis.</p></div

A comparative analysis of the molecular basis of fibrosis between tissues

The aim of effective healing is to restore comparable structure and function to tissues. In some circumstances, this is not achieved, resulting in fibrotic scar tissue formation. Although this may have offered survival advantages in the past, fibrosis leads to functional disruption, organ failure and even death. Fibrosis affects many tissues types, but its ramifications are arguably most conspicuous in the skin. Dermal fibrosis impacts millions of people worldwide, and currently, treatment is not directed against a given molecular abnormality. Research demonstrates a complex picture of cellular and molecular interaction culminating in the deposition of fibrotic tissue. This article discusses key molecular mechanisms of fibrosis within tissues and highlights the similarities and differences amongst key pathways. There is compelling evidence for the involvement of toll-like receptor-4 and transforming growth factor β within fibrosis throughout all tissue types. With regards to other molecules, although there are similarities between tissues, evidence is inconsistent. In order to gain therapeutic advances in the prevention or treatment of fibrosis, research should strive to understand specific molecular mechanisms in models that closely replicate human disease. Further, there should be a healthy scepticism regarding the applicability of given molecular targets between settings. This review highlights a number of prime movers to fibrosis that are the focus of current research