Abstract
Fc gamma receptor IIb (FcgRIIb) is the only inhibitory-FcgR in the FcgR family, and FcgRIIb-deficient (FcgRIIb−/−) mice develop a lupus-like condition with hyper-responsiveness against several stimulations. The activation of aryl hydrocarbon receptor (Ahr), a cellular environmental sensor, might aggravate activity of the lupus-like condition. As such, 1,4-chrysenequinone (1,4-CQ), an Ahr-activator, alone did not induce supernatant cytokines from macrophages, while the 24 h pre-treatment by lipopolysaccharide (LPS), a representative inflammatory activator, prior to 1,4-CQ activation (LPS/1,4-CQ) predominantly induced macrophage pro-inflammatory responses. Additionally, the responses from FcgRIIb−/− macrophages were more prominent than wild-type (WT) cells as determined by (i) supernatant cytokines (TNF-α, IL-6, and IL-10), (ii) expression of the inflammation associated genes (NF-κB, aryl hydrocarbon receptor, iNOS, IL-1β and activating-FcgRIV) and cell-surface CD-86 (a biomarker of M1 macrophage polarization), and (iii) cell apoptosis (Annexin V), with the lower inhibitory-FcgRIIb expression. Moreover, 8-week-administration of 1,4-CQ in 8 week old FcgRIIb−/− mice, a genetic-prone lupus-like model, enhanced lupus characteristics as indicated by anti-dsDNA, serum creatinine, proteinuria, endotoxemia, gut-leakage (FITC-dextran), and glomerular immunoglobulin deposition. In conclusion, an Ahr activation worsened the disease severity in FcgRIIb−/− mice possibly through the enhanced inflammatory responses. The deficiency of inhibitory-FcgRIIb in these mice, at least in part, prominently enhanced the pro-inflammatory responses. Our data suggest that patients with lupus might be more vulnerable to environmental pollutants.
Highlights
Aryl hydrocarbon receptor (Ahr), a cytosol receptor, [1,2,3,4,5,6] is a natural sensor for either the exogenous factors, including polyaromatic hydrocarbons and environmental toxins, or the oxygen-related endogenous factors [7]
Polycyclic aromatic hydrocarbons (PAHs) in the particulate matter of air pollution [8,9] induce lung injury and systemic inflammation [10] through aryl hydrocarbon receptor (Ahr) activation [11,12,13] are demonstrated in several studies [1,3]
Ahr signaling is escalated in macrophages that are pre-conditioned by mycobacterial infection [17] and the exposure to polycyclic aromatic hydrocarbons (PAHs) accelerates serum inflammatory markers [11]
Summary
Aryl hydrocarbon receptor (Ahr), a cytosol receptor, [1,2,3,4,5,6] is a natural sensor for either the exogenous factors, including polyaromatic hydrocarbons and environmental toxins, or the oxygen-related endogenous factors [7]. Polycyclic aromatic hydrocarbons (PAHs) in the particulate matter of air pollution [8,9] induce lung injury and systemic inflammation [10] through Ahr activation [11,12,13] are demonstrated in several studies [1,3]. Ahr activation produces both pro- [11] and anti-inflammatory effects [1,3,14,15] possibly depending on the cell microenvironment. Inflammation enhances the pollutant effects [16], and the pollutants amplified inflammatory responses [7]. Macrophages are major innate immune cells that are responsible for the pollutants-induced inflammation, possibly due to their professional phagocytosis activity and cytokine production [19,20,21]. Among phagocytic cells (macrophages, neutrophils, and dendritic cells) [22,23], macrophages (referred to as “sentinel immune cells”)
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