Exposure to Diesel Exhaust Particle Extracts (DEPe) Impairs Some Polarization Markers and Functions of Human Macrophages through Activation of AhR and Nrf2

Abstract

Macrophages (MΦ), well-known to play an important role in immune response, also respond to environmental toxic chemicals such as diesel exhaust particles (DEP). Potential effects of DEPs towards MΦ polarization, a key hall-mark of MΦ physiology, remain however poorly documented. This study was therefore designed to evaluate the effects of a reference DEP extract (DEPe) on human MΦ polarization. Human blood monocytes-derived MΦ were incubated with IFNγ+LPS or IL-4 to obtain M1 and M2 subtypes, respectively; a 24 h exposure of polarizing MΦ to 10 μg/ml DEPe was found to impair expression of some macrophagic M1 and M2 markers, without however overall inhibition of M1 and M2 polarization processes. Notably, DEPe treatment increased the secretion of the M1 marker IL-8 and the M2 marker IL-10 in both MΦ subtypes, whereas it reduced lipopolysaccharide-induced IL-6 and IL-12p40 secretion in M1 MΦ. In M2 MΦ, DEPe exposure led to a reduction of CD200R expression and of CCL17, CCL18 and CCL22 secretion, associated with a lower chemotaxis of CCR4-positive cells. DEPe activated the Nrf2 and AhR pathways and induced expression of their reference target genes such as Hmox-1 and cytochrome P-4501B1 in M1 and M2 MΦ. Nrf2 or AhR silencing through RNA interference prevented DEPe-related down-regulation of IL-6. AhR silencing also inhibited the down-secretion of IL-12p40 and CCL18 in M1- and M2-DEPe-exposed MΦ, respectively. DEPs are therefore likely to alter expression of some M1 and M2 markers in an AhR- and Nrf2-dependent manner; such regulations may contribute to deleterious immune effects of atmospheric DEP.

Comparison of in vitro toxicological effects of biomass smoke from different sources of animal dung

“…The aryl hydrocarbon receptor (AhR) is a key transcription factor involved in pulmonary immune responses to urban combustion products, including diesel exhaust and tobacco smoke (19, 30, 31). To investigate whether different types of animal dung biomass smoke contain ligands of the AhR, we used a well-characterized AhR activity assay utilizing mouse liver cells with a luciferase reporter (23, 25, 32, 33).…”

“…Important regulators of airway inflammatory responses to inhaled pollutants that we assessed with dung biomass smoke exposure were the AhR and AP-1 (19, 30, 31). Similar to previous work examining the effects of dung smoke by us and others, we found that six different types of dung biomass smoke can activate the AhR (Figure 5) and AP-1 (Figure 6) in human airway epithelial cells (6, 8).…”

Pulmonary macrophages: key players in the innate defence of the airways

“…Although cigarette smoke shares similar characteristics to particulate pollution, exposure to cigarette smoke has been shown to skew macrophages towards an M2 phenotype 44. Treatment of polarised human monocyte derived M1 and M2 macrophages with diesel exhaust particles impairs expression of some M1 and M2 markers without overall inhibition of the polarisation process while increasing secretion of the M1 and M2 cytokines IL-8 and IL-10, respectively, via activation of Ahr and Nrf2 91. Although lung macrophages orchestrate the inflammatory responses induced by exposure to air pollutants resulting in adverse lung and cardiovascular effects, it remains to be determined which factors such as size and composition of particulate matter determine macrophage polarisation.…”

Maternal administration of nanomaterials elicits hemoglobin upregulation in the neonatal brain of non-human primates

“…Increased levels of the HbA protein were also observed in the hippocampi of subjects in the DEP group. A recent report indicated that DEP extract can activate Nrf2 and aryl hydrocarbon receptor (AhR) pathways in vitro (Jaguin et al, 2015). Thus, nanoparticles such as DEP induce oxidative or inflammatory stress, which likely results in Nrf2 activation in the fetal/neonatal brain.…”