Aryl Hydrocarbon Receptor (AhR) Regulates Silica-Induced Inflammation But Not Fibrosis

Abstract

The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, is responsible for mediating a variety of pharmacological and toxicological effects caused by halogenated aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). However, recent evidence has revealed that the AhR also has numerous physiological roles aside from xenobiotic metabolism, including regulation of immune and inflammatory signaling as well as normal development and homeostasis of several organs. To investigate the role of the AhR in crystalline silica (SiO(2))-induced inflammation and fibrosis, C57Bl/6 and AhR(-/)(-) mice were exposed to SiO(2) or vehicle. Similarly, C57Bl/6 mice were exposed to SiO(2) and TCDD either simultaneously or sequentially to assess whether AhR activation alters inflammation and fibrosis. SiO(2)-induced acute lung inflammation was more severe in AhR(-)(/-) mice; however, the fibrotic response of AhR(-)(/-) mice was attenuated compared with C57Bl/6 mice. In a model of chronic SiO(2) exposure, AhR activation by TCDD in C57Bl/6 mice resulted in reduced inflammation; however, the fibrotic response was not affected. Bone marrow-derived macrophages (BMM) from AhR(-)(/-) mice also produced higher levels of cytokines and chemokines in response to SiO(2). Analysis of gene expression revealed that BMM derived from AhR(-)(/-) mice exhibit increased levels of pro-interleukin (IL)-1β, IL-6, and Bcl-2, yet decreased levels of signal transducers and activators of transcription (STAT)2, STAT5a, and serpin B2 (Pai-2) in response to SiO(2).

IL-33 mediates multi-walled carbon nanotube (MWCNT)-induced airway hyper-reactivity via the mobilization of innate helper cells in the lung

“…Transpulmonary resistance (R L ) and dynamic compliance (C dyn ) were directly measured by pulmonary mechanics on sedated, ventilated subjects as previously described (Wells et al 2008; Beamer et al 2010; Beamer et al 2012). Mice were challenged with vehicle, followed by increasing concentrations of methacholine (1.5, 3, 6, 12, and 24 mg/ml).…”

Cytokine responses induced by diesel exhaust particles are suppressed by PAR-2 silencing and antioxidant treatment, and driven by polar and non-polar soluble constituents

“…Thus, AhR-activation by classical PAHs or other AhR-ligands does not appear to be the driving force in DEP-induced inflammation in this cell line. Indeed recent findings suggest that AhR ligands may rather suppress pro-inflammatory responses by other agents (Beamer et al, 2012;Furumatsu et al, 2011;Øvrevik et al, 2014). However, PAHs with lower affinity for the AhR may possibly contribute to DEP-induced cytokine/chemokine responses through other mechanisms (Mayati et al, 2014;Øvrevik et al, 2013).…”

Role of the aryl hydrocarbon receptor (AhR) in lung inflammation

“…Although normal activation of the Nlrp3 inflammasome contributes to host defense, excessive activation leads to auto-inflammatory diseases. Thus, it is of particular interest that macrophages derived from AhR deficient mice secrete elevated levels of IL-1β, and that activation of the AhR with TCDD reduces SiO 2 -induced increases in IL-1β levels in vitro and in vivo , ultimately reducing pulmonary inflammation (43). Furthermore, the AhR has been implicated in the regulation of inflammasome adaptor proteins including Pai-2 and STAT2 (123–125), such that select AhR ligands may induce signaling cascades that negatively regulate inflammasome activation and ultimately effect inflammation and fibrosis in the lungs.…”