Nramp1 Promotes Efficient Macrophage Recycling of Iron Following Phenylhydrazine-Induced Hemolytic Anemia
Bibliographic record
Abstract
Abstract Natural resistance-associated macrophage protein 1 (Nramp1) is a divalent metal transporter expressed exclusively in phagocytic cells such as macrophages and neutrophils. Based on our earlier in vitro study (Soe-Lin et al. Exp Hematol.2008;36:929–937), we hypothesize that Nramp1 may participate in the recycling of iron acquired through the phagocytosis of senescent red blood cells by macrophages. In order to examine the effect of Nramp1 on iron recycling in vivo, the iron parameters of wildtype (Nramp1+/+) and Nramp1 knockout mice (Nramp1−/−) were analyzed following both acute and chronic induction of hemolytic anemia by phenylhydrazine treatment. We observe that untreated Nramp1−/− mice exhibited greater serum transferrin saturation and splenic iron content, higher duodenal ferroportin (Fpn) and divalent metal transporter 1 (DMT1) expression, and dramatically lower hepcidin mRNA levels than untreated Nramp1+/+ mice. Significant iron loading of the reticuloendothelial organs was found to increase with age in knockout mice. Following acute treatment with the hemolytic agent phenylhydrazine, Nramp1−/− mice experienced a significant decrease in serum iron levels and hematocrit, while their Nramp1+/+ counterparts were relatively unaffected. Following a month-long phenylhydrazine regimen, Nramp1−/− mice retained markedly increased quantities of iron within the liver and spleen, and exhibited greater splenomegaly and reticulocytosis than wild-type mice. Furthermore, while hepcidin mRNA levels decreased following chronic phenylhydrazine treatment in both Nramp1+/+ and Nramp1−/− mice, this effect was significantly more pronounced in Nramp1−/− mice. The data presented in this report suggest that in the absence of Nramp1, iron accumulates to a greater degree within reticuloendothelial organs such as the liver and spleen following acute and chronic hemolytic anemia. We hypothesize that the low hepcidin mRNA levels seen in Nramp1−/− mice are a response to a diminished availability of iron for erythropoiesis resulting from the aberrant increase in iron retention within their splenic reticuloendothelial macrophages. Our observation of increased DMT1 and ferroportin within the duodenums of the Nramp1−/− animals imply that the increase in transferrin saturation despite the impaired iron release from erythrophagocytosing macrophages occurs due to a compensatory increase in iron absorption from the diet. These findings are consistent with our hypothesis that Nramp1 promotes the efficient recycling of iron in erythrophagocytosing macrophages.
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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) | 0.000 | 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) | 0.001 | 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 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".