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.
Highlights
Previous epidemiological studies have indicated that exposure to ambient particulate matter (PM) is linked to increase in mortality and morbidity related to cardio-pulmonary diseases [1]
Among the 10 classically activated M1 MF markers analysed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), we found an induction of TNFα, cyclooxygenase-2 and IL-8 and a significant down-regulation of the chemokines CXCL10 and CXCL11 and of the aminoacid transporter SLC7A5 in DEP extract (DEPe)-treated M1 MF when compared to their untreated counterpart (Fig. 1A); by contrast, mRNA expression of the M1 markers CCL5, BIRC3, ICAM and indoleamine-pyrrole 2,3-dioxygenase (IDO1) remained unchanged in response to DEPe (Fig. 1A)
For the 12 alternative activated M2 MF markers analysed by RT-qPCR, we found a significant up-regulation of TGF-β and fatty acid binding protein 4 (FABP4), and a down-regulation of CCL17, CCL18, mannose receptor (MRC1), peroxisome proliferator-activated receptor γ (PPARγ) and nitric oxide synthase 3 (NOS3) in DEPe-treated M2 MF when compared to their untreated counterparts (Fig. 1B); by contrast, mRNA levels of other typical M2 markers such as IL-10, scavenger receptor B1 (SR-B1), CD36, cyclooxygenase-1 (PTGS1) and tenascin C (TNC) were not modified in M2 MF exposed to DEPe (Fig. 1B)
Summary
Previous epidemiological studies have indicated that exposure to ambient particulate matter (PM) is linked to increase in mortality and morbidity related to cardio-pulmonary diseases [1]. Diseases [2], and to progression of atherosclerosis in both animal experimental models and humans [3] Such adverse effects are more closely associated to PM with a diameter less than 2.5 μm (PM2.5) such as diesel exhaust particulates (DEP) containing adsorbed organic compounds, and to their ability to increase the release of pro-inflammatory mediators by epithelial, endothelial cells and immune cells, leading to inflammation. DEP extracts (DEPe) have been shown to activate AhR and to increase pro-inflammatory cytokine expression in the human monocytic U937 cell line [6]; they induce intracellular ROS generation through CYP system in MF and human airway epithelial cells [11,12]. Our results indicate that exposure to DEPe impaired expression of some macrophagic M1 and M2 markers, in an AhR- and Nrf2-dependent manner
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