A80 MALT1 BLOCKS IL-1β-MEDIATED INTESTINAL INFLAMMATION
Bibliographic record
Abstract
Primary immune deficiencies are often accompanied by intestinal inflammation. A patient with severe combined immunodeficiency and dramatic inflammation along the gastrointestinal tract was diagnosed with a homozygous mutation in MALT1. Malt1 acts both as a scaffolding protein and a protease. The consequences of MALT1 immunodeficiency have largely been attributed to its role in lymphocytes. However, macrophages play an important role in gut inflammation and Malt1 is activated in macrophages downstream of toll-like receptor 4 and dectin-1. The effect of MALT1 deficiency in macrophages and its contribution to gut inflammation has not been investigated. We hypothesized that Malt1 deficiency in murine macrophages increases susceptibility to DSS-induced colitis by increasing pro-inflammatory cytokine production. To address this hypothesis, we will determine: 1) whether Malt1 deficient mice are more susceptible to DSS-induced intestinal inflammation than wild type mice, and 2) the role of Malt1 expression and activity in pro-inflammatory macrophage responses. Malt1+/+ and Malt1-/- mice were subjected to DSS-induced colitis and sacrificed for histology, immunohistochemistry, and tissue cytokine analyses by ELISA. Malt1+/+ or Malt1-/- murine bone marrow-derived macrophages were differentiated with macrophage colony-stimulating factor and wild type macrophages were untreated or treated with the Malt1 inhibitor mepazine; followed by stimulation with LPS or curdlan. Cytokines were assayed by ELISA and whole cell lysates were analyzed by western blot, and in a Malt1 activity assay. In vivo, Malt1 deficiency exacerbated DSS-induced colitis in mice. Macrophage stimulation increased Malt1 protein expression but decreased Mat1 activity. Malt1 deficient murine macrophages produced more IL-1β than wild type macrophages and pharmacological inhibition of Malt1 protease activity increased some pro-inflammatory cytokine production in response to innate immune stimuli. Taken together, our studies suggest that Malt1 deficiency contributes to intestinal inflammation in vivo by increasing macrophage pro-inflammatory cytokine production. In future studies, we will investigate the cell-specific contribution of Malt1 deficiency in macrophages using myeloid-specific Malt1-/- mice. These studies will provide critical information about the cell specific role of Malt1 and possible side effects of MALT1 inhibitors currently used for lymphoma treatment. CIHRBCCHR Graduate Award
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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) | 0.000 | 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) | 0.003 | 0.001 |
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".