The RIPK3-IL-6 axis mediates kidney injury in cytokine storm syndrome
Bibliographic record
Abstract
Receptor-interacting protein kinase 3 (RIPK3) is best known as a mediator of necroptosis, a regulated necrosis pathway observed in diseases with high inflammatory components. We explored the role of RIPK3 in cytokine storm syndrome (CSS)-induced acute kidney injury induced by lipopolysaccharide (LPS) in wild-type and Ripk3-deficient mice. For the in vitro experiments, we treated both primary tubular epithelial cells and bone marrow-derived cells from wild-type and Ripk3-deficient mice with LPS. Ripk3 deficiency improved renal function and increased survival in CSS, a common condition observed in severe infections and other scenarios, and protection was associated with reduced inflammation. Mechanistically, the necroptosis pathway did not play a key role in kidney protection by Ripk3 deficiency, and the NLRP3 inflammasome was partially implicated. Olink plasma proteomics identified IL-6 as the most upregulated inflammatory protein in the kidney and circulation, and it was most responsive to Ripk3 deficiency. Ripk3-deficient mice had suppressed kidney, liver, and lung Il-6 expression as well as suppressed kidney activation of STAT3, a transcription factor downstream of IL-6. In bone marrow chimeric mice, RIPK3-expressing bone marrow-derived cells were required to drive IL-6 expression, and AKI and kidney Il-6 expression correlated with loss of renal function. In this regard, in vitro experiments have shown that RIPK3 mediates Il-6 expression in bone marrow cells but not in tubular cells. Additionally, targeting the IL-6 receptor improves kidney function and reduces kidney inflammation in CSS-AKI. Kidney transcriptomic data of human AKI associated with COVID-19 CSS were consistent with activation of the RIPK3-IL-6 axis. The RIPK3-IL-6 axis in bone marrow cells mediates systemic inflammation and kidney injury induced by a cytokine storm, independent of the necroptosis and inflammasome pathways. Specific targeting of bone marrow RIPK3 may limit kidney inflammation, without the potential adverse effects of systemic RIPK3 targeting.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 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 | 0.001 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".