Granzyme K: An Important Mediator of Cutaneous Inflammation and Re‐epithelialization
Bibliographic record
Abstract
Background Granzyme K (GzmK) is a serine protease traditionally thought as having a role in immune cell‐mediated killing. However, recent evidence has challenged this paradigm. We now believe GzmK is a mediator of inflammation. GzmK is elevated in plasma from patients with a variety of pro‐inflammatory disorders, including allergic asthma, endotoxemia, and sepsis. In addition, culture of endothelial cell, lung fibroblasts and activated macrophages with purified GzmK induces the secretion of pro‐inflammatory cytokines. In the present study we hypothesized that GzmK is elevated in cutaneous inflammation and contributes to impaired reepithelialization of cutaneous wounds. Methods GzmK expression was evaluated histologically in tissue from patients with a variety of inflammatory skin diseases and compared to healthy skin controls. Using a murine model of skin injury and repair, the role of GzmK was investigated. Wound severity was assessed macroscopically, comparing onset, severity and wound resolution between GzmK−/− and wildtype mice. Wound tissue was isolated and examined histologically, including wound morphometry (wound area, re‐epithelialization, epidermal thickness), GzmK expression, collagen organization (Masson's Trichrome, picosirius red, Collage I/III), inflammation (markers of T‐cells, macrophages, NK cells), angiogenesis (CD31) and fibrosis (α‐SMA). To further verify the role of GzmK in cutaneous inflammation, cultured keratinocytes and skin fibroblasts were exposed to GzmK and cytokine expression, cellular proliferation and viability were assessed. Results GzmK was markedly increased in biopsies from patients with skin wounds compared to normal skin, with negligible levels observed. Macrophages, namely classically activated M1, were identified as the predominant cell type responsible for GzmK expression and secretion. GzmK−/− mice exhibited expedited wound closure and wound maturation compared to equivalent wounds in wild‐type mice. Re‐epithelialization had the greatest disparity between GzmK−/− and wild‐type mice; vastly accelerated epithelialization observed in GzmK−/− mice suggests that keratinocytes may be particularly sensitive to GzmK insult. Additionally, in vitro cultured keratinocytes exhibited impaired wound healing, including decreased cell migration and viability, and an increase in pro‐inflammatory cytokines when exposed to GzmK. Conclusion GzmK is an important mediator of cutaneous inflammation and epithelialization; functioning to enhance the pro‐inflammatory phase of wound repair whilst simultaneously hindering re‐epithelialization. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 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".