Macrophage Migration Inhibitory Factor and Hypoxia-Inducible Factor 1-Alpha May Play a Role in Maintaining Intestinal Homeostasis Through Regulation of Occludin and Claudin-1 Expression
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Bibliographic record
Abstract
Objectives Axial spondyloarthritis (axSpA) is a chronic inflammatory condition mainly impacting the musculoskeletal system. The majority of axSpA patients experience gut inflammation, with 60% having microscopic changes and 10% having overt inflammatory bowel disease (IBD). Over the years, researchers have linked many pathways and cell populations to the pathogenesis of gut inflammation in axSpA. One notable player may be the macrophage migration inhibitory factor (MIF), a crucial factor in axSpA development. In a SpA mouse model (SKG mice), MIF overexpression mirrors key clinical features of axSpA, while inhibiting or depleting MIF attenuates these symptoms. It is believed that MIF and hypoxia-inducible factor 1 alpha (HIF-1α) have a functional interdependence. Nevertheless, the precise role of MIF and HIF in gut inflammation in axSpA remains uncertain. Here we aimed to investigate the MIF-HIF interaction’s impact on gut homeostasis and inflammation in the SKG mouse model. Methods Eight weeks old SKG mice were used for this 4-arm study, with 3 mice per arm: SKG control mice, SKG mice treated with curdlan, SKG-MIF Knock Out (KO), and SKG-MIFKO mice treated with curdlan. After 8 weeks of curdlan/vehicle treatment, 16 weeks old mice were euthanized, and formalin-fixed paraffin-embedded (FFPE) blocks of ileum were prepared for immunohistochemistry (IHC). IHC was performed to assess the tight junction markers, occludin and claudin-1 and, HIF-1α expression. Kruskal-Wallis test was used to analyze the difference between the 4 groups. Results SKG-MIFKO mice showed reduced occludin and claudin-1 expression, indicating tight junction disruption (Figure 1). HIF-1α expression decreased significantly in SKG-MIFKO and SKG-MIFKO+curdlan groups. Notably, HIF-1α expression decreased further in SKG-MIFKO+curdlan compared to SKG+curdlan, with a trend of higher expression in SKG+curdlan compared to controls (Figure 1). Conclusion Knocking out MIF in SKG mice has resulted in a notable improvement in axSpA symptoms. However, our findings show that MIF has a protective role in the gut of SKG mice, which is unlike what we see in joints. In the absence of MIF, there was a decrease in the expression of tight junction markers and HIF-1 α, which suggests that the interaction between MIF and HIF is essential for maintaining the integrity of the gut epithelial barrier in the SKG mouse model of SpA. Further investigation is required to determine the role of HIF-1α in transcriptional regulation of tight junction markers.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it