Alternatively activated macrophages protect mice during induced intestinal inflammation
Bibliographic record
Abstract
Inflammatory bowel disease (IBD) is an idiopathic disease characterized by chronic intestinal inflammation and ulceration. Canada has the highest incidence of IBD in the world with 1 in 150 people affected. While treatment options target symptoms and attempt to dampen down inflammation, an increasing population of patients is refractory to current therapeutic options. Macrophages are heterogeneous in their functions and while it is clear that inflammatory macrophages contribute to inflammation in IBD, multiple lines of evidence suggest that alternatively activated macrophages may offer protection during intestinal inflammation. In vivo SHIP deficient mouse macrophages are alternatively activated so SHIP deficient mice provide a unique genetic model of alternative macrophage activation. Using the dextran sodium sulfate (DSS)-induced model of colitis, I found that SHIP-/- mice are protected during induced intestinal inflammation, the protection is macrophage mediated, and can be conferred to a susceptible host. To determine how SHIP contributes to alternative activation of macrophages, I demonstrate that SHIP-deficient murine macrophages are more sensitive to IL-4-mediated skewing to an alternatively activated phenotype. Moreover, SHIP levels are reduced in alternatively activated macrophages and this is required for alternative activation because it is dependent on PI3K activity. Arginase (ArgI) induction is specifically dependent on the PI3Kp110δ isoform of class IA PI3K. As such, mice deficient in PI3Kp110δ catalytic subunit activity have increased clinical disease activity and histological damage during DSS-induced colitis. Colitis severity correlates with reduced numbers of ArgI+ M2 macrophages in the colon, increased nitric oxide production, and is macrophagedependent. Importantly, adoptive transfer of IL-4-treated macrophages from wild type mice, but not from PI3Kp110δ deficient mice, protects mice during DSS-induced colitis. Protection is lost when mice are treated with inhibitors that block arginase activity showing that ArgI activity is required for M2 macrophage-mediated protection from intestinal inflammation. These findings identify SHIP and the PI3K pathway as critical regulators of alternative macrophage activation and as potential targets for manipulation in IBD. In addition, adoptive transfer of alternatively activated macrophages to patients with IBD also offers a promising, new strategy for treatment that may be particularly useful in patients who are refractory to conventional therapies.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.005 |
| 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".