Exposure to Diesel Exhaust Particle Extracts (DEPe) Impairs Some Polarization Markers and Functions of Human Macrophages through Activation of AhR and Nrf2
February
Exposure to Diesel Exhaust Particle Extracts (DEPe) Impairs Some Polarization Markers and Functions of Human Macrophages through Activation of AhR and Nrf2
Marie Jaguin 0 1 2
Olivier Fardel 0 1 2
Valrie Lecureur 0 1 2
0 1 UMR INSERM U1085, Institut de Recherche sur la Sante, l'Environnement et le Travail (IRSET), Universite de Rennes 1 , 2 avenue du Pr Leon Bernard, 35043, Rennes, France, 2 Pole Biologie, Centre Hospitalier Universitaire (CHU) Rennes, 2 rue Henri Le Guilloux, 35033, Rennes , France
1 Funding: This work was supported by Fondation Coeur et Arteres (FCA 09T3), Institut National de la Sante et de la Recherche Medicale and the University of Rennes 1. MJ is a recipient of a fellow from the French Ministry of Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
2 Academic Editor: Carolyn J. Baglole, McGill University , CANADA
Macrophages (M), 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 M polarization, a key hall-mark of M physiology, remain however poorly documented. This study was therefore designed to evaluate the effects of a reference DEP extract (DEPe) on human M polarization. Human blood monocytes-derived M were incubated with IFN+LPS or IL-4 to obtain M1 and M2 subtypes, respectively; a 24 h exposure of polarizing M to 10 g/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 M subtypes, whereas it reduced lipopolysaccharide-induced IL-6 and IL-12p40 secretion in M1 M. In M2 M, 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 P4501B1 in M1 and M2 M. 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 M, 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.
-
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].
Moreover, urban air pollution may contribute to exacerbations of asthma and to allergic airway
Competing Interests: The authors have declared
that no competing interests exist.
diseases [2], but also 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 m (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.
Monocytes and macrophages (MF) play a key role in innate and adaptive immunity and
inflammation. After release from bone marrow to blood, monocytes are recruited to tissues
where, according to the nature of environmental signals, they can develop into myeloid
dendritic cells or various forms of MF. The classically activated MF or M1 type generated by
IFN followed by LPS stimulation produce high pro-inflammatory cytokines such as TNF
and IL-12/IL-23 and play a role in tissue destruction [4]. In contrast, IL-4- or IL-13-stimulated
MFs, so-called M2 MF or alternative activated MF, express membrane receptors such as
scavenger receptors and mannose receptor CD206, fail to produce IL-12 cytokine but they
release anti-inflammatory cytokines like IL-10 and IL-1RA and some Th2 chemokines such as
CCL17 (TARC), CCL18 (PARC) and CCL22 (MDC); such M2 MF are involved in tissue
remodelling and wound repair [45]. Overall, type M1 MF support the Th1 response whereas
type M2 MFs support of Th2 response.
Interestingly, DEP have been shown to up-regulate both pro-inflammatory mediators and
antioxidant enzymes in various cells, including MF, which appear as a key cell type targeted by
DEP [67]. DEP have also immunosuppressive effects through reducing cytokine release,
notably by alveolar MF [810]. Mechanisms involved in DEP effects towards MF are however
poorly understood. Two main families of compounds adsorbed on DEP, polycyclic aromatic
hydrocarbons (PAH) and quinones, are likely to contribute to them, at least in part.
Mechanistically, PAHs bind to the cytosolic aryl hydrocarbon receptor (AhR), which then migrates to
the nucleus wher (...truncated)