NOX4 Expression in Human Microglia Leads to Constitutive Generation of Reactive Oxygen Species and to Constitutive IL-6 Expression
Bibliographic record
Abstract
Reactive oxygen species (ROS) generation by microglia is implicated in neuroinflammation and neurotoxicity, as well as in host defense, cell proliferation and excitatory amino acid release. Recent studies demonstrate that primary microglia preparations not only express the phagocyte NADPH oxidase NOX2, but also the NOX1 and NOX4 isoforms. Here we investigated the relationship between neuroinflammation and NOX isoform expression in the human microglia cell line clone 3 (HMC3). HMC3 cells are typical microglia, as suggested by the constitutive expression of Iba-1 and CD14, and IFN-gamma-induced expression of CD11b, CD68 and MHCII. However, the characteristics of NOX isoform expression and ROS generation by HMC3 cells were unexpected. RT-PCR demonstrated abundant expression of NOX4, but almost no NOX2 mRNA. ROS generation was constitutive and appeared predominantly intracellular, as superoxide was detected within intracellular vesicles, while the cell-permeable H(2)O(2) was found in the extracellular space. ROS generation by HMC3 was efficiently suppressed by siRNA directed against NOX4, but not by control siRNA. NOX4 suppression did not alter expression of the microglia-typical genes MHCII, CD68 and CD11b, nor did it affect the expression of iNOS, VEGF or TGF-beta. However, there was a marked decrease in IL-6 mRNA. Taken together, we demonstrate a constitutive NOX4-dependent ROS generation in a microglial cell line which leads to expression of IL-6 mRNA. The possibility that microglia could switch from tightly regulated NOX2-dependent ROS generation to constitutive NOX4-dependent ROS generation is of interest for the understanding of the role of microglia in maintaining the balance between neuroprotection and neuroinflammatory damage.
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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".