ArticleClinical and translational medicine2025
The antiprotease Spink7 promotes inflammation resolution by modulating multiple proteases activities during wound healing.
Article in Clinical and translational medicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- The Serine Protease-Serine Protease Inhibitor Regulatory Network in Inflammatory Bowel Disease: From Molecular Mechanisms to Novel Therapeutic Horizons.Journal of advanced research · 2026Review
- SPINK2 in hematopoiesis and cancer: Biology and clinical implications.Cell death discovery · 2026Review
- High-dose irradiation promotes macrophage-mediated engulfment of triple-negative breast cancer through M1 polarization via the IKZF1-CCL5 axis.Cell communication and signaling : CCS · 2026Article
- Neutrophil Irg1/itaconate axis protects against experimental colitis by suppressing local inflammation and maintaining hematopoietic homeostasis.Molecular biomedicine · 2025Article
- The SPINK Protein Family in Cancer: Emerging Roles in Tumor Progression, Therapeutic Resistance, and Precision Oncology.Pharmaceuticals (Basel, Switzerland) · 2025Review
- The antiprotease Spink7 promotes inflammation resolution by modulating multiple proteases activities during wound healing.Clinical and translational medicine · 2025Article
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Authors and funding
8 authors.
Funding
Abstract
backgroundEffective control of inflammation is crucial for the healing of cutaneous wounds, but the molecular mechanisms governing inflammation resolution during wound closure are still not yet clear. Here, we describe a homeostatic mechanism that facilitates the inflammation resolution by timely regulating the targeted proteases activities through antiprotease Spink7 (serine peptidase inhibitor, kazal type 7).
methodsThe expression pattern of Spink7 was investigated by quantitative RT-PCR, immunohistochemistry (IHC) and in situ hybridization. In both Spink7 knockdown and knockout models, quantitative comparisons were made between the healing rate of wounds and histopathological morphometric analysis. Microarrays, multiple chemokine assays, IHC, immunofluorescence, protease activity measurement were performed to explore the underlying mechanisms of Spink7 knockout in impaired wound healing. Radiation-wound combined injury (R-W-CI) model was employed to evaluate the therapeutic effects of Spink7 manipulation.
resultsOur study demonstrates that Spink7 is significantly upregulated in the differentiated epidermal granular keratinocytes of proliferative phase during murine wound closure. Both local knockdown of Spink7 levels in wounds using siRNA gel and systemic knockout of Spink7 using KO mice resulted in delayed wound closure with sustained neutrophil infiltration. Loss of Spink7 leads to augmented inflammatory responses, increased production of multiple chemokines/cytokines, and impaired M2 polarization of macrophages in wound healing. Furthermore, loss of Spink7 results in elevated proteolytic activities of uPA, MMP2/9 and KLK5/7 in proliferative phase. However, inhibiting KLK5/7 downstream PAR2 activation exacerbates the phenotype of KO mice. In R-W-CI model, further significant induction of Spink7 is observed in wounds with insufficient inflammatory response. Local suppression of Spink7 promotes wound healing in the R-W-CI model by augmenting inflammation.
conclusionsMaintaining an endogenous balance between Spink7 and its target proteases is a crucial checkpoint for regulating inflammation resolution during healing. Therefore, manipulating levels of Spink7 might be an effective treatment for impaired wounds caused by inflammatory dysregulation.
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