Ship Represses the PI3-Kinase-Mediated Skewing of Myeloid Cell Development towards Alternative (M-2) Macrophages.
Bibliographic record
Abstract
Abstract Macrophages possess the remarkable ability to orchestrate both the initiation and resolution phases of inflammation. The initial inflammatory response is carried out by classically-activated, or killer (M-1) macrophages, which eradicate invading microorganisms and tumour cells, while the resolution phase is carried out by alternatively-activated, or healing (M-2) macrophages, which are normally involved in wound healing. Paradoxically, macrophages within tumours (tumour-associated macrophages, TAMs) or from patients with severe or chronic inflammation behave like M-2 macrophages (i.e. they are hypo-responsive to pro-inflammatory stimuli). In the case of severe/chronic inflammation this is thought to be an adaptation to avoid damage to the host. However, in the case of cancer M-2 skewing enables tumours to exploit the healing properties of this subclass of macrophages for tumour growth and immune system evasion. Despite these observations and the great therapeutic potential of harnessing macrophage polarization, the mechanisms of macrophage programming have yet to be fully elucidated. Interestingly, mice deficient in the SH2-containing inositol-5′-phosphatase, SHIP (a master negative regulator of PI3-kinase in the immune system) possess a dramatic overabundance of M-2 macrophages. As a result, SHIP−/− peritoneal macrophages (as opposed to wild-type C57Bl/6 macrophages, which have an M-1 preponderance) can not be induced to synthesize high levels of nitric oxide (NO). This is because they constitutively express very high levels of arginase I, an M-2 enzyme which competes with inducible nitric oxide synthase (iNOS) for the common substrate, L-arginine, thereby diverting L-arginine metabolism to the healing intermediates, polyamines and proline (to enhance DNA synthesis and collagen formation, respectively). Further support for this M-2 skewing comes from the observation that SHIP−/− lungs are filled with macrophage-associated, extracellular crystals, likely composed of the chitinase-like secretory lectin, Ym1, another M-2 macrophage product which often spontaneously crystallizes in chronically inflamed lungs and is thought to be involved in lung healing. Consistent with these findings, subcutaneously injected M27 Lewis lung carcinoma cells grow more rapidly in the more tumour-friendly, M-2-skewed environment of the SHIP−/− mouse than in wild-type littermates. Interestingly, while we demonstrate that M-2 skewing in SHIP−/− mice is a response to their heightened, spontaneous inflammation, we also show that the absence of SHIP lowers the threshold for M-2 macrophage skewing, even in response to endogenous factors found in non-inflamed, normal mouse plasma. Specifically, we find that this in vivo M-2 skewing can be mimicked in vitro by adding wild-type mouse plasma to the standard bone marrow cultures used to generate SHIP−/− macrophages, but not by adding mouse plasma to naively-differentiated, already-mature SHIP−/− bone marrow macrophages. Thus, SHIP represses the PI3-kinase-mediated skewing of myeloid cell development towards alternatively (M-2) activated macrophages and this may hold therapeutic value in cancer and chronic inflammation.
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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) | 0.004 | 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".