DOWNREGULATION OF YTHDF2 IN THE SPINAL DORSAL HORN CONTRIBUTES TO THE GENESIS OF CHRONIC PAIN INDUCED BY SYSTEMIC LUPUS ERYTHEMATOSUS
Bibliographic record
Abstract
PV246 / #544 Poster Topic: AS24 - SLE-Treatment Background/Purpose Chronic pain is a common and significant issue for patients with systemic lupus erythematosus (SLE) due to the limited effectiveness and safety of current analgesics. There is an urgent need to identify new and effective targets for managing SLE-associated chronic pain. Gaining insight into the cellular and molecular mechanisms driving SLE-induced chronic pain is essential to advance effective therapies. In studies using an SLE mouse model (MRL/lpr mice), we identified spinal neuroinflammation and abnormal neuronal activity as key contributors to chronic pain in SLE mice. Given the critical role of the YT521-B homology domain family 2 (YTHDF2) RNA-binding protein in epitranscriptomic regulation in neurological disorders, uncovering whether and how the YTHDF2 pathway regulates chronic pain in SLE mice could provide a promising new strategy for managing SLE-induced pain. Methods A spontaneous SLE mouse model, MRL/lpr mice, and their controls (MRL mice) were used. Behavioral tests were used to assess pain perception in the mice. Protein signaling molecules were analyzed using Western blotting and immunohistochemistry. Intrathecal injection of siRNA was used to manipulate gene expression in the spinal dorsal horn. Results Female MRL/lpr mice had an increased hind paw volume (an indicator of arthritis) from 12 weeks of age, as measured using a water displacement plethysmometer. Meanwhile, lupus mice spontaneously developed hypersensitivity in their hind paws to radiant heat stimuli starting at 12 to 13 weeks of age, reaching a plateau between 14 and 16 weeks. Mechanical hypersensitivity (allodynia) emerged in the hind paws at 14 weeks and persisted through 16 weeks. Western blotting analysis showed that YTHDF2 protein levels in the spinal dorsal horn of MRL/lpr mice were significantly lower than those in control mice. Using immunohistochemistry techniques, we found that YTHDF2 protein is expressed in neurons, astrocytes and microglia in the spinal dorsal horn. Knockdown of YTHDF2 protein expression in the dorsal horn of normal control mice by intrathecal injection of YTHDF2 siRNA (1 μg/injection, b.i.d. for 2 days) induced thermal hyperalgesia and mechanical allodynia. This was accompanied by significantly increased neuronal activation, as evidenced by elevated c-fos protein and phosphorylated extracellular signal-regulated kinase (ERK) expression, as well as microglial activation indicated by increased ionized calcium binding adaptor molecule 1 (Iba1) protein expression, and astrocyte activation evidenced by increased glial fibrillary acidic protein (GFAP) expression in the dorsal horn. These were concurrently accompanied by elevated phosphorylated-P38 activity, IL-1β, and IL-18 levels, along with reduced glial glutamate transporter-1 protein expression in the same area. The molecular and behavioral alterations induced by spinal YTHDF2 knockdown mimic those observed in lupus mice. Conclusions Our results suggest that downregulation of YTHDF2 in the spinal dorsal horn contributes to the genesis of lupus-induced chronic pain through regulating spinal neuroinflammation and neuronal activation.
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How this classification was reachedexpand
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 | 0.004 | 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 | 0.000 |
| 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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".