<scp>LRRC8A</scp>is dispensable for a variety of microglial functions and response to acute stroke
Bibliographic record
Abstract
Microglia, resident brain immune cells, are critical in orchestrating responses to central nervous system (CNS) injury. Many microglial functions, such as phagocytosis, motility and chemotaxis, are suggested to rely on chloride channels, including the volume-regulated anion channel (VRAC), but studies to date have relied on the use of pharmacological tools with limited specificity. VRAC has also been proposed as a drug target for acute CNS injury, and its role in microglial function is of considerable interest for developing CNS therapeutics. This study aimed to definitively confirm the contribution of VRAC in microglia function by using conditional LRRC8A-knockout mice, which lacked the essential VRAC subunit LRRC8A in microglia. We demonstrated that while VRAC contributed to cell volume regulation, it had no effect on phagocytic activity, cell migration or P2YR12-dependent chemotaxis. Moreover, loss of microglial VRAC did not affect microglial morphology or the extent of ischemic damage following stroke. We conclude that VRAC does not critically regulate microglial responses to brain injury and could be targetable in other CNS cell types (e.g., astrocytes) without impeding microglial function. Our results also demonstrate a role for VRAC in cell volume regulation but show that VRAC is not involved in several major cellular functions that it was previously thought to regulate, and point to other, alternative mechanisms of chloride transport in innate immunity.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.002 |
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 source (direct Gemma or distilled Codex), 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".