Lipopolysaccharide-Enhanced Responses against Aryl Hydrocarbon Receptor in FcgRIIb-Deficient Macrophages, a Profound Impact of an Environmental Toxin on a Lupus-Like Mouse Model

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.

Interference on Cytosolic DNA Activation Attenuates Sepsis Severity: Experiments on Cyclic GMP–AMP Synthase (cGAS) Deficient Mice

“…Interestingly, serum cfDNA in CLP consists of host DNA and bacterial DNA, while cfDNA in the LPS model consists mainly of host cell cfDNA. Indeed, bacterial DNA (and endotoxemia) in CLP mice is responsible from bacteremia, and gut bacterial translocation causes endotoxemia in CLP mice [ 52 , 53 ], while levels of microbial DNA in the LPS model might be lower because bacteremia is undetectable in the LPS model [ 47 , 54 ]. Then, the less profound CLP severity and the less severe responses against LPS injection in cGAS -/- mice compared with WT imply an impact of cfDNA from host cells and organisms (in the CLP model) and cfDNA mainly from host cells (in the LPS model), respectively.…”

“…After 24 h incubation, supernatant cytokines (TNF-α, IL-6 and IL-10) and cyclic guanosine monophosphate–adenosine monophosphate (2’3’-cGAMP) were determined by enzyme-linked immunosorbent assay (ELISA) from Invitrogen and Cayman Chemical (Ann Arbor, MI, USA), respectively. The cells were collected in parallel to evaluate gene expression by real-time quantitative reverse transcription polymerase chain reaction (qRT–PCR), as previously described [ 47 , 54 ]. Accordingly, total RNA was prepared by Trizol, quantified by NanoDrop ND-1000 (Thermo Fisher Scientific), converted into cDNA by Reverse Transcription System) and qPCR was performed using SYBR Green system (Applied Biosystem, Foster City, CA, USA).…”

Lactobacillus rhamnosus attenuates Thai chili extracts induced gut inflammation and dysbiosis despite capsaicin bactericidal effect against the probiotics, a possible toxicity of high dose capsaicin

“…Because of bactericidal activity of capsaicin (a major chili active-component) [ 65 ], chili-induced gut inflammation might, at least in part, be due to gut dysbiosis. Indeed, chili extracts induced gut dysbiosis as indicated by increased Bacteroides, the Gram-negative anaerobes with a possible pathogenesis [ 51 ], decreased Firmicutes, the predominant organisms in healthy condition [ 51 ], and enhanced fecal total Gram-negative bacteria, a source of LPS (a potent pro-inflammatory inducer) in gut [ 60 – 62 , 66 ], without an alteration in Proteobacteria, the pathogenic Gram-negative aerobes [ 51 ] ( Fig 3A–3D ). However, chili extracts did not alter neither the variety of microorganisms (Chao and Shannon indexes of alpha diversity) nor microbe abundance in gut as the values of the total OTUs ( Fig 3E ).…”

Lactobacillus plantarum Outperforms Enterococcus faecium on Anti-obesity Possibly through the Differences in Gut Dysbiosis Attenuation, Despite the Similar Anti-inflammatory Properties

“…Due to the influence of probiotics on gut inflammation [46][47][48] and the importance of macrophages on inflammation [49,50], an impact of condition media from L. plantarum or E. faecium were also tested in macrophages. Accordingly, bone marrow-derived macrophages were isolated from femurs and tibias of mice following a previous protocol [46].…”