Pro-dermcidin and derivatives as potential therapeutics for lethal experimental sepsis
A 110-amino acid precursor of dermcidin (pre-dermcidin, pre-DCD) with a 19-residue N-terminal leader signal sequence can be secreted by human eccrine sweat glands as a leader-less pro-domain-containing peptide (pro-DCD), which is enzymatically cleaved to generate C-terminal anti-microbial peptides (...
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Frontiers Media S.A.
2025-06-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1621633/full |
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| author | Weiqiang Chen Weiqiang Chen Xiaoling Qiang Xiaoling Qiang Cassie Shu Zhu Cassie Shu Zhu Jianhua Li Li Lou Ping Wang Ping Wang Kevin J. Tracey Kevin J. Tracey Haichao Wang Haichao Wang |
| author_facet | Weiqiang Chen Weiqiang Chen Xiaoling Qiang Xiaoling Qiang Cassie Shu Zhu Cassie Shu Zhu Jianhua Li Li Lou Ping Wang Ping Wang Kevin J. Tracey Kevin J. Tracey Haichao Wang Haichao Wang |
| author_sort | Weiqiang Chen |
| collection | DOAJ |
| description | A 110-amino acid precursor of dermcidin (pre-dermcidin, pre-DCD) with a 19-residue N-terminal leader signal sequence can be secreted by human eccrine sweat glands as a leader-less pro-domain-containing peptide (pro-DCD), which is enzymatically cleaved to generate C-terminal anti-microbial peptides (dermcidin-1, DCD-1) capable of killing various bacteria. Previously, it was unknown whether pro-DCD could be pharmacologically developed as potential therapeutics for lethal sepsis. Here, we demonstrated that pharmacological suppression of pro-DCD with polyclonal antibodies worsened sepsis-induced inflammation and liver injury, whereas supplementation of pro-DCD or its PEGylation derivatives significantly protected against sepsis, even when given 2–24 h after disease onset. These protective effects were associated with a significant reduction in circulating levels of surrogate biomarkers [e.g., Granulocyte Colony Stimulating Factor (G-CSF), Interleukin-6 (IL-6), keratinocytes-derived chemokine (KC), Monocyte Chemoattractant Protein 1 (MCP-1), Macrophage Inflammatory Protein-2 (MIP-2), and Soluble Tumor Necrosis Factor Receptor I (sTNFRI)], tissue injury, and blood bacterial counts. Although pro-DCD or its PEGylation derivatives failed to directly kill bacteria across a wide range of concentrations, they were able to activate microtubule-associated protein 1A/1B-light chain 3 (LC3), a marker of autophagy and phagosome maturation in LC3-associated bacterial phagocytosis. Our findings suggest that pro-DCD-derived agents hold promise as potential therapies for clinical sepsis. |
| format | Article |
| id | doaj-art-23fbb8b9384d420ab8b50822100b39a9 |
| institution | OA Journals |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-23fbb8b9384d420ab8b50822100b39a92025-08-20T02:01:58ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-06-011610.3389/fimmu.2025.16216331621633Pro-dermcidin and derivatives as potential therapeutics for lethal experimental sepsisWeiqiang Chen0Weiqiang Chen1Xiaoling Qiang2Xiaoling Qiang3Cassie Shu Zhu4Cassie Shu Zhu5Jianhua Li6Li Lou7Ping Wang8Ping Wang9Kevin J. Tracey10Kevin J. Tracey11Haichao Wang12Haichao Wang13The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United StatesDepartments of Emergency Medicine and/or Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United StatesThe Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United StatesDepartments of Emergency Medicine and/or Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United StatesThe Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United StatesDepartments of Emergency Medicine and/or Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United StatesThe Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United StatesThe Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United StatesThe Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United StatesDepartments of Emergency Medicine and/or Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United StatesThe Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United StatesDepartments of Emergency Medicine and/or Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United StatesThe Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United StatesDepartments of Emergency Medicine and/or Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United StatesA 110-amino acid precursor of dermcidin (pre-dermcidin, pre-DCD) with a 19-residue N-terminal leader signal sequence can be secreted by human eccrine sweat glands as a leader-less pro-domain-containing peptide (pro-DCD), which is enzymatically cleaved to generate C-terminal anti-microbial peptides (dermcidin-1, DCD-1) capable of killing various bacteria. Previously, it was unknown whether pro-DCD could be pharmacologically developed as potential therapeutics for lethal sepsis. Here, we demonstrated that pharmacological suppression of pro-DCD with polyclonal antibodies worsened sepsis-induced inflammation and liver injury, whereas supplementation of pro-DCD or its PEGylation derivatives significantly protected against sepsis, even when given 2–24 h after disease onset. These protective effects were associated with a significant reduction in circulating levels of surrogate biomarkers [e.g., Granulocyte Colony Stimulating Factor (G-CSF), Interleukin-6 (IL-6), keratinocytes-derived chemokine (KC), Monocyte Chemoattractant Protein 1 (MCP-1), Macrophage Inflammatory Protein-2 (MIP-2), and Soluble Tumor Necrosis Factor Receptor I (sTNFRI)], tissue injury, and blood bacterial counts. Although pro-DCD or its PEGylation derivatives failed to directly kill bacteria across a wide range of concentrations, they were able to activate microtubule-associated protein 1A/1B-light chain 3 (LC3), a marker of autophagy and phagosome maturation in LC3-associated bacterial phagocytosis. Our findings suggest that pro-DCD-derived agents hold promise as potential therapies for clinical sepsis.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1621633/fullinnate immune cellspro-dermcidinPEGylationanti-bacterialanti-inflammationLC3 activation |
| spellingShingle | Weiqiang Chen Weiqiang Chen Xiaoling Qiang Xiaoling Qiang Cassie Shu Zhu Cassie Shu Zhu Jianhua Li Li Lou Ping Wang Ping Wang Kevin J. Tracey Kevin J. Tracey Haichao Wang Haichao Wang Pro-dermcidin and derivatives as potential therapeutics for lethal experimental sepsis Frontiers in Immunology innate immune cells pro-dermcidin PEGylation anti-bacterial anti-inflammation LC3 activation |
| title | Pro-dermcidin and derivatives as potential therapeutics for lethal experimental sepsis |
| title_full | Pro-dermcidin and derivatives as potential therapeutics for lethal experimental sepsis |
| title_fullStr | Pro-dermcidin and derivatives as potential therapeutics for lethal experimental sepsis |
| title_full_unstemmed | Pro-dermcidin and derivatives as potential therapeutics for lethal experimental sepsis |
| title_short | Pro-dermcidin and derivatives as potential therapeutics for lethal experimental sepsis |
| title_sort | pro dermcidin and derivatives as potential therapeutics for lethal experimental sepsis |
| topic | innate immune cells pro-dermcidin PEGylation anti-bacterial anti-inflammation LC3 activation |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1621633/full |
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