Mouse connective tissue mast cell proteases tryptase and carboxypeptidase A3 play protective roles in itch induced by endothelin-1
Abstract Background Itch is an unpleasant sensation that can be debilitating, especially if it is chronic and of non-histaminergic origin, as treatment options are limited. Endothelin-1 (ET-1) is a potent endogenous vasoconstrictor that also has the ability to induce a burning, non-histaminergic pru...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2020-04-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12974-020-01795-4 |
| _version_ | 1818528096404373504 |
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| author | Elín I. Magnúsdóttir Mirjana Grujic Jessica Bergman Gunnar Pejler Malin C. Lagerström |
| author_facet | Elín I. Magnúsdóttir Mirjana Grujic Jessica Bergman Gunnar Pejler Malin C. Lagerström |
| author_sort | Elín I. Magnúsdóttir |
| collection | DOAJ |
| description | Abstract Background Itch is an unpleasant sensation that can be debilitating, especially if it is chronic and of non-histaminergic origin, as treatment options are limited. Endothelin-1 (ET-1) is a potent endogenous vasoconstrictor that also has the ability to induce a burning, non-histaminergic pruritus when exogenously administered, by activating the endothelin A receptor (ETAR) on primary afferents. ET-1 is released endogenously by several cell-types found in the skin, including macrophages and keratinocytes. Mast cells express ETARs and can thereby be degranulated by ET-1, and mast cell proteases chymase and carboxypeptidase A3 (CPA3) are known to either generate or degrade ET-1, respectively, suggesting a role for mast cell proteases in the regulation of ET-1-induced itch. The mouse mast cell proteases (mMCPs) mMCP4 (chymase), mMCP6 (tryptase), and CPA3 are found in connective tissue type mast cells and are the closest functional homologs to human mast cell proteases, but little is known about their role in endothelin-induced itch. Methods In this study, we evaluated the effects of mast cell protease deficiency on scratching behavior induced by ET-1. To investigate this, mMCP knock-out and transgenic mice were injected intradermally with ET-1 and their scratching behavior was recorded and analyzed. Results CPA3-deficient mice and mice lacking all three proteases demonstrated highly elevated levels of scratching behavior compared with wild-type controls. A modest increase in the number of scratching bouts was also seen in mMCP6-deficient mice, while mMCP4-deficiency did not have any effect. Conclusion Altogether, these findings identify a prominent role for the mast cell proteases, in particular CPA3, in the protection against itch induced by ET-1. |
| first_indexed | 2024-12-11T06:45:11Z |
| format | Article |
| id | doaj.art-6256e3a9110446bfbb257fc4039b052b |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-12-11T06:45:11Z |
| publishDate | 2020-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-6256e3a9110446bfbb257fc4039b052b2022-12-22T01:17:06ZengBMCJournal of Neuroinflammation1742-20942020-04-0117111110.1186/s12974-020-01795-4Mouse connective tissue mast cell proteases tryptase and carboxypeptidase A3 play protective roles in itch induced by endothelin-1Elín I. Magnúsdóttir0Mirjana Grujic1Jessica Bergman2Gunnar Pejler3Malin C. Lagerström4Department of Neuroscience, Uppsala UniversityDepartment of Medical Biochemistry and Microbiology, Uppsala UniversityDepartment of Neuroscience, Uppsala UniversityDepartment of Medical Biochemistry and Microbiology, Uppsala UniversityDepartment of Neuroscience, Uppsala UniversityAbstract Background Itch is an unpleasant sensation that can be debilitating, especially if it is chronic and of non-histaminergic origin, as treatment options are limited. Endothelin-1 (ET-1) is a potent endogenous vasoconstrictor that also has the ability to induce a burning, non-histaminergic pruritus when exogenously administered, by activating the endothelin A receptor (ETAR) on primary afferents. ET-1 is released endogenously by several cell-types found in the skin, including macrophages and keratinocytes. Mast cells express ETARs and can thereby be degranulated by ET-1, and mast cell proteases chymase and carboxypeptidase A3 (CPA3) are known to either generate or degrade ET-1, respectively, suggesting a role for mast cell proteases in the regulation of ET-1-induced itch. The mouse mast cell proteases (mMCPs) mMCP4 (chymase), mMCP6 (tryptase), and CPA3 are found in connective tissue type mast cells and are the closest functional homologs to human mast cell proteases, but little is known about their role in endothelin-induced itch. Methods In this study, we evaluated the effects of mast cell protease deficiency on scratching behavior induced by ET-1. To investigate this, mMCP knock-out and transgenic mice were injected intradermally with ET-1 and their scratching behavior was recorded and analyzed. Results CPA3-deficient mice and mice lacking all three proteases demonstrated highly elevated levels of scratching behavior compared with wild-type controls. A modest increase in the number of scratching bouts was also seen in mMCP6-deficient mice, while mMCP4-deficiency did not have any effect. Conclusion Altogether, these findings identify a prominent role for the mast cell proteases, in particular CPA3, in the protection against itch induced by ET-1.http://link.springer.com/article/10.1186/s12974-020-01795-4ItchChymaseCarboxypeptidase A3TryptaseMice |
| spellingShingle | Elín I. Magnúsdóttir Mirjana Grujic Jessica Bergman Gunnar Pejler Malin C. Lagerström Mouse connective tissue mast cell proteases tryptase and carboxypeptidase A3 play protective roles in itch induced by endothelin-1 Journal of Neuroinflammation Itch Chymase Carboxypeptidase A3 Tryptase Mice |
| title | Mouse connective tissue mast cell proteases tryptase and carboxypeptidase A3 play protective roles in itch induced by endothelin-1 |
| title_full | Mouse connective tissue mast cell proteases tryptase and carboxypeptidase A3 play protective roles in itch induced by endothelin-1 |
| title_fullStr | Mouse connective tissue mast cell proteases tryptase and carboxypeptidase A3 play protective roles in itch induced by endothelin-1 |
| title_full_unstemmed | Mouse connective tissue mast cell proteases tryptase and carboxypeptidase A3 play protective roles in itch induced by endothelin-1 |
| title_short | Mouse connective tissue mast cell proteases tryptase and carboxypeptidase A3 play protective roles in itch induced by endothelin-1 |
| title_sort | mouse connective tissue mast cell proteases tryptase and carboxypeptidase a3 play protective roles in itch induced by endothelin 1 |
| topic | Itch Chymase Carboxypeptidase A3 Tryptase Mice |
| url | http://link.springer.com/article/10.1186/s12974-020-01795-4 |
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