Effect of tumor necrosis factor inhibition on spinal inflammation and spinal ankylosis in SKG mice

Lim, Doo-Ho; Lee, Eun Ju; Kwon, Oh Chan; Hong, Sungeun; Lee, Chang Keun; Yoo, Bin; Youn, Jeehee; Kim, So Yeon

doi:10.1038/s41598-019-54549-5

Cited by 9 publications

(5 citation statements)

References 47 publications

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“…Within 3 weeks after the first curdlan injection, SKG mice developed inflammatory arthritis with swelling and redness in peripheral joints as previously reported [22]. The PBS-injected SKG mice did not show any features of joint inflammation.…”

Section: Effect Of Plag On Arthritissupporting

confidence: 84%

“…These mice have a mutation in the gene encoding of the SH2 domain of ZAP-70, a key signal transduction molecule in T cells. This mutation results in a failure in the negative selection of highly self-reactive T cells [ 22 ]. We previously showed that after a curdlan injection, SKG mice develop lung inflammation, fibrosis, arthritis and lung lesions [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

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Acetylated Diacylglycerol 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol in Autoimmune Arthritis and Interstitial Lung Disease in SKG Mice

Lim

Lee

et al. 2021

Biomedicines

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Acetylated diacylglycerol 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) is a lipid molecule from the antlers of sika deer that might reduce inflammation by effectively controlling neutrophil infiltration, endothelial permeability and inflammatory chemokine production. Therefore, we evaluated the modulatory effect of PLAG on arthritis and interstitial lung disease (ILD) in an autoimmune arthritis model. We injected curdlan into SKG mice and PLAG was orally administered every day from 3 weeks to 20 weeks after the curdlan injection. The arthritis score was measured every week after the curdlan injection. At 20 weeks post-injection, the lung specimens were evaluated with H&E, Masson’s trichrome and multiplexed immunofluorescent staining. Serum cytokines were also analyzed using a Luminex multiple cytokine assay. PLAG administration decreased the arthritis score until 8 weeks after the curdlan injection. However, the effect was not sustained thereafter. A lung histology revealed severe inflammation and fibrosis in the curdlan-induced SKG mice, which was attenuated in the PLAG-treated mice. Furthermore, immunofluorescent staining of the lung tissue showed a GM-CSF+ neutrophil accumulation and a decreased citrullinated histone 3 expression after PLAG treatment. PLAG also downregulated the levels of IL-6 and TNF-α and upregulated the level of sIL-7Rα, an anti-fibrotic molecule. Our results indicate that PLAG might have a preventative effect on ILD development through the resolution of NETosis in the lung.

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Section: Effect Of Plag On Arthritissupporting

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Acetylated Diacylglycerol 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol in Autoimmune Arthritis and Interstitial Lung Disease in SKG Mice

Lim

Lee

et al. 2021

Biomedicines

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“…This dynamic between pro-in ammatory and regulatory pathways highlights the potential of targeting these cytokines in therapeutic strategies. Modulating the activity of TNF-β and IL-6, through targeted biological agents, has shown e cacy in reducing AS in ammation and improving patient outcomes, illustrating the importance of understanding the cytokine balance in AS management (43,44).…”

Section: Discussionmentioning

confidence: 99%

Unraveling New Therapeutic Targets in Ankylosing Spondylitis: Multi-Omics Mendelian Randomization on Immune Cells, Metabolites, and Inflammation Proteins

Du,

Li,

Zhang

et al. 2024

Preprint

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Objective: To identify novel immunological, metabolic, and inflammatory determinants of Ankylosing Spondylitis (AS) using Mendelian Randomization (MR), offering new insights into its pathogenesis and potential therapeutic interventions. Methods: Employing a bidirectional, secondary validation two-sample MR (TSMR), this study investigated causal associations among 1,400 serum metabolites, 731 immune cell traits, and 91 circulating inflammatory proteins with AS. Instrumental variables (IVs) were identified using PLINK for minimal linkage disequilibrium, applying strict significance thresholds. Various MR methodologies, including Inverse Variance Weighted (IVW), Weighted Median, and MR-Egger, were applied to validate causal links. Sensitivity analyses, incorporating heterogeneity and pleiotropy tests, were performed to evaluate the robustness of the results. The False Discovery Rate (FDR) correction was applied to adjust for multiple comparisons, while the MR Steiger directionality test and bidirectional MR analysis validated the causation direction. Secondary validation with data from diverse sources was undertaken to confirm the reliability of the findings. Results: After FDR correction, associations were identified between AS etiology and 9 immune cell traits, 2 serum metabolites, and 2 inflammatory proteins. Notably, the presence of CX3CR1 on monocytes and the absolute count (AC) of CD62L- CD86+ myeloid Dendritic Cells (DCs) were associated with an increased risk of AS. In contrast, expression of HLA DR on DCs, including myeloid and plasmacytoid DCs, and on CD14- CD16- monocytes, along with CD64 expression across various monocyte subsets (monocytes, CD14+ CD16+, and CD14+ CD16-), correlated with a decreased risk of AS development. Serum metabolites, specifically levels of Hexadecanedioate (C16-DC) and Bilirubin (E, Z or Z, E), were also linked to a reduced risk of AS. Regarding inflammatory factors, Interleukin-6 levels were inversely associated with AS morbidity, whereas TNF-beta levels were positively correlated with higher AS morbidity. Neither bidirectional MR nor MR Steiger tests provided evidence supporting reverse causation. Conclusion: This study sheds light on the complex interactions between immune cells traits, metabolites, and inflammatory proteins in AS, offering new insights into its pathophysiology. The findings underscore the importance of the immune-metabolic-inflammation network in AS, suggesting novel biomarkers for diagnosis and targets for therapy.

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“…These mice have a point mutation involving the SH2 domain in the gene encoding ZAP-70, a key signal transduction molecule in T cells [28]. They tend, especially when exposed to a beta-glucan such as a curdlan, to develop peripheral arthritis in the early stage and spinal ankylosis in the late stage due to the development of autoreactive T cells that signal at least in part via IL-17A/IL-22 and IL-23 [29,30]. In line with previous studies, the IL-17A + and FOXP3 + IL-17A + cells were increased in our curdlan-administered SKG mice.…”

Section: Discussionmentioning

confidence: 99%

“…SKG mice provide a better model of human SpA, as they display peripheral arthritis, enthesitis, and inflammatory bowel disease [27]. These mice have a point mutation in the SH2 domain of ZAP-70, a gene encoding a key signal transduction molecule in T cells [28].They have the potential to cause peripheral arthritis at an early stage and spinal ankylosis at a later stage, due to the development of autoreactive T cells, in part as a result of IL-17A/IL-22 and IL-23 signaling, and they are especially sensitive to beta-glucans such as curdlan [29,30]. Curdlan, a β-glucan polymer, is synthesized by various bacterial genera, notably Agrobacterium, Alcaligenes, and Rhizobium, and is able to stimulate Toll-like receptor 2 (TLR2) signaling and, consequently, to induce a Th17 cell-mediated immune response.…”

Section: Introductionmentioning

confidence: 99%

The Expression of the Alpha7 Nicotinic Acetylcholine Receptor and the Effect of Smoking in Curdlan-Administered SKG Mice

Kim,

Lee,

Lee

et al. 2023

Biomedicines

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Nicotine, an abundant molecule in tobacco, has immunomodulatory effects on inflammatory diseases, primarily due to the activation of alpha7 nicotinic acetylcholine receptor (α7 nAChR). We aim to evaluate the expression of the α7 nAChR+ cells in joint tissue and the effect of smoking on immune cells and peripheral arthritis in curdlan-administered SKG mice, a murine model of spondyloarthropathy (SpA). The SKG mice were injected with curdlan two times at 2-week intervals and were divided into two groups; one exposed to cigarette smoke and the other not exposed. We found that the α7 nAChR+ cells increased in the joint tissue of curdlan-administered SKG mice compared to in the wild type. Furthermore, the peripheral arthritis scores and histological scores for synovial inflammation were lower in smoke-exposed curdlan-administered SKG mice than in mice not exposed to smoke. Immunofluorescence staining of the α7 nAChR+ and IL-17A+ cells was lower in the synovia of smoke-exposed mice than the control mice. The proportions of α7 nAChR+IL-17A+ and α7 nAChR+IL-17A+FOXP3+ cells also decreased in the synovia of smoke-exposed mice compared with the controls. We observed an increase in the α7 nAChR+ cells within the joint tissue of curdlan-administered SKG mice and that cigarette smoke had an influence on both peripheral arthritis and immune cell population, especially α7 nAChR+ cells. Thus, exposure to cigarette smoke after arthritogenic stimuli may have an anti-arthritogenic effect in curdlan-administered SKG mice.

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Effect of tumor necrosis factor inhibition on spinal inflammation and spinal ankylosis in SKG mice

Cited by 9 publications

References 47 publications

Acetylated Diacylglycerol 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol in Autoimmune Arthritis and Interstitial Lung Disease in SKG Mice

Acetylated Diacylglycerol 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol in Autoimmune Arthritis and Interstitial Lung Disease in SKG Mice

Unraveling New Therapeutic Targets in Ankylosing Spondylitis: Multi-Omics Mendelian Randomization on Immune Cells, Metabolites, and Inflammation Proteins

The Expression of the Alpha7 Nicotinic Acetylcholine Receptor and the Effect of Smoking in Curdlan-Administered SKG Mice

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