The antiprotease Spink7 promotes inflammation resolution by modulating multiple proteases activities during wound healing
Abstract Background Effective 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...
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Wiley
2025-04-01
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| Series: | Clinical and Translational Medicine |
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| Online Access: | https://doi.org/10.1002/ctm2.70291 |
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| author | Na Zhao Guojian Wang Shuang Long Xiaofan Lv Xinze Ran Junping Wang Yongping Su Tao Wang |
| author_facet | Na Zhao Guojian Wang Shuang Long Xiaofan Lv Xinze Ran Junping Wang Yongping Su Tao Wang |
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| description | Abstract Background Effective 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). Methods The 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. Results Our 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. Conclusions Maintaining 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. |
| format | Article |
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| institution | OA Journals |
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| language | English |
| publishDate | 2025-04-01 |
| publisher | Wiley |
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| series | Clinical and Translational Medicine |
| spelling | doaj-art-2aa8385e2c5a43a1a4f93bb4a955ca182025-08-20T02:16:21ZengWileyClinical and Translational Medicine2001-13262025-04-01154n/an/a10.1002/ctm2.70291The antiprotease Spink7 promotes inflammation resolution by modulating multiple proteases activities during wound healingNa Zhao0Guojian Wang1Shuang Long2Xiaofan Lv3Xinze Ran4Junping Wang5Yongping Su6Tao Wang7Institute of Combined Injury Chongqing Engineering Research Center for Nanomedicine School of Preventive Military Medicine Army Medical University (Third Military Medical University) Chongqing ChinaInstitute of Combined Injury Chongqing Engineering Research Center for Nanomedicine School of Preventive Military Medicine Army Medical University (Third Military Medical University) Chongqing ChinaInstitute of Combined Injury Chongqing Engineering Research Center for Nanomedicine School of Preventive Military Medicine Army Medical University (Third Military Medical University) Chongqing ChinaInstitute of Combined Injury Chongqing Engineering Research Center for Nanomedicine School of Preventive Military Medicine Army Medical University (Third Military Medical University) Chongqing ChinaInstitute of Combined Injury Chongqing Engineering Research Center for Nanomedicine School of Preventive Military Medicine Army Medical University (Third Military Medical University) Chongqing ChinaInstitute of Combined Injury Chongqing Engineering Research Center for Nanomedicine School of Preventive Military Medicine Army Medical University (Third Military Medical University) Chongqing ChinaInstitute of Combined Injury Chongqing Engineering Research Center for Nanomedicine School of Preventive Military Medicine Army Medical University (Third Military Medical University) Chongqing ChinaInstitute of Combined Injury Chongqing Engineering Research Center for Nanomedicine School of Preventive Military Medicine Army Medical University (Third Military Medical University) Chongqing ChinaAbstract Background Effective 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). Methods The 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. Results Our 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. Conclusions Maintaining 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.https://doi.org/10.1002/ctm2.70291inflammation resolutionproteasesradiation‐wound combined injurySpink7wound healing |
| spellingShingle | Na Zhao Guojian Wang Shuang Long Xiaofan Lv Xinze Ran Junping Wang Yongping Su Tao Wang The antiprotease Spink7 promotes inflammation resolution by modulating multiple proteases activities during wound healing Clinical and Translational Medicine inflammation resolution proteases radiation‐wound combined injury Spink7 wound healing |
| title | The antiprotease Spink7 promotes inflammation resolution by modulating multiple proteases activities during wound healing |
| title_full | The antiprotease Spink7 promotes inflammation resolution by modulating multiple proteases activities during wound healing |
| title_fullStr | The antiprotease Spink7 promotes inflammation resolution by modulating multiple proteases activities during wound healing |
| title_full_unstemmed | The antiprotease Spink7 promotes inflammation resolution by modulating multiple proteases activities during wound healing |
| title_short | The antiprotease Spink7 promotes inflammation resolution by modulating multiple proteases activities during wound healing |
| title_sort | antiprotease spink7 promotes inflammation resolution by modulating multiple proteases activities during wound healing |
| topic | inflammation resolution proteases radiation‐wound combined injury Spink7 wound healing |
| url | https://doi.org/10.1002/ctm2.70291 |
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