6-formylindolo[3, 2-b]carbazole alters gut microbiota and prevents the progression of ankylosing spondylitis in mice.

Ankylosing spondylitis (AS), is known as a chronic inflammatory autoimmune disease, there is evidence to suggest that gut microbiota disorders may be related to the occurrence and development of AS. Studies have shown that 6-formylindolo[3, 2-b]carbazole (FICZ) has the ability to modulate intestinal homeostasis and inhibit inflammatory responses. The purpose of this work is to evaluate the protective role of FICZ in treating AS and elucidate potential mechanisms. FICZ was administered to the proteoglycan (PG)-induced AS mice for 7 consecutive weeks. The effects of FICZ on AS mice were evaluated by the disease severity, intestinal histopathology, proinflammatory cytokine levels, and intestinal mucosal barrier function. The gut microbiota compositions were profiled through 16S rDNA high-throughput sequencing. We found that FICZ significantly reduced the severity of AS and resulted in the downregulating of TNF-α and IL-17A inflammatory cytokines. Moreover, FICZ ameliorated pathological changes in the ileal and improved intestinal mucosal barrier function. Furthermore, FICZ altered the composition of the gut microbiota by increasing the Bacteroidetes/Firmicutes phylum ratio and enriched the genes related to "glycan biosynthesis and metabolism", thus reversing the process of AS. In conclusion, FICZ suppressed the progression of AS and altered gut microbiota in AS mice, which provided new insight into AS therapy strategy.

Ankylosing spondylitis PET imaging and quantifications via P2X7 receptor-targeting radioligand [18F]GSK1482160.

PURPOSE: Ankylosing spondylitis (AS) is a chronic inflammatory disease of the axial spine; however, the quantitative detection of inflammation in AS remains a challenge in clinical settings. We aimed to investigate the feasibility of using a specific P2X7R-targeting 18F-labeled tracer [18F]GSK1482160 for positron emission tomography (PET) imaging and the quantification of AS. METHODS: The radioligand [18F]GSK1482160 was obtained based on nucleophilic aliphatic substitution. Dynamic [18F]GSK1482160 and [18F]FDG micro-PET/CT imaging were performed on AS mice (n = 8) and age-matched controls (n = 8). Tracer kinetics modeling was performed using Logan's graphical arterial input function analysis to quantify the in vivo expression of P2X7R. The post-PET tissues were collected for hematoxylin-eosin (H&E), immunohistochemical (IHC), and immunofluorescence (IF) staining. RESULTS: [18F]GSK1482160 PET/CT imaging revealed that the specific binding in the ankle joint and sacroiliac joint (SIJ) of the AS at 8 weeks group (BPNDankle-AS-8W (non-displaceable binding potential of the ankle) 3.931 ± 0.74; BPND SIJ-AS-8W (BPBD of the SIJ) 4.225 ± 0.84) were significantly higher than the controls at 8 weeks group (BPNDankle-Ctr-8W 0.325 ± 0.15, BPNDSJJ-Ctr-8W 0.319 ± 0.17) respectively, and the AS at 14 weeks group (BPNDankle-AS-14W 12.212 ± 2.25; BPNDSJJ-AS-14W 13.389 ± 3.60) were significantly higher than the controls at 14 weeks group (BPNDankle-Ctr-14W 0.204 ± 0.16, BPNDSJJ-Ctr-14W 0.655 ± 0.35) respectively. The four groups had no significant difference in the [18F]FDG uptake of ankle and SIJ. IHC and IF staining revealed that the overexpression of P2X7R was colocalized with activated macrophages from the ankle synovium and spinal endplate in mice with AS, indicating that quantification of P2X7R may contribute to the understanding of the pathogenesis of inflammation in human AS. CONCLUSION: This study developed a novel P2X7R-targeting PET tracer [18F]GSK1482160 to detect the expression of P2X7R in AS mouse models and provided powerful non-invasive PET imaging and quantification for AS.

Fluid shear stress modulates endothelial inflammation by targeting LIMS2.

Mechanosensitive genes regulate multiple cardiovascular pathophysiological processes and disorders; however, the role of flow-sensitive genes in atherosclerosis is still unknown. In this study, we identify LIM Zinc Finger Domain Containing 2 (LIMS2) that acts as a mechanosensitive gene downregulated by disturbed flow (d-flow) both in human endothelial cells (ECs) in vitro and in mice in vivo. Mechanistically, d-flow suppresses LIMS2 expression, which leads to endothelial inflammation by upregulating typical inflammatory factors, VCAM-1, and ICAM-1 in human ECs. The findings indicate that LIMS2, the new flow-sensitive gene, may help us to find a new insight to explain how d-flow caused endothelial inflammation and provide a new therapeutic approach for atherosclerosis in the future.