Pathogenic roles and therapeutic potential of the CCL8–CCR8 axis in a murine model of IgG4-related sialadenitis
Abstract Background Our previous studies reveal that CCL18-CCR8 chemokine axis is upregulated in patients of immunoglobulin G4-related disease (IgG4-RD), suggesting that the CCL18–CCR8 axis is implicated in the etiology of IgG4-RD, although whether this axis has a potential as a therapeutic target r...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2021-08-01
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| Series: | Arthritis Research & Therapy |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13075-021-02597-6 |
| _version_ | 1819138220685787136 |
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| author | Fumika Honda Hiroto Tsuboi Yuko Ono Saori Abe Hiroyuki Takahashi Kiyoaki Ito Kazunori Yamada Mitsuhiro Kawano Yuya Kondo Kenichi Asano Masato Tanaka Marie Malissen Bernard Malissen Isao Matsumoto Takayuki Sumida |
| author_facet | Fumika Honda Hiroto Tsuboi Yuko Ono Saori Abe Hiroyuki Takahashi Kiyoaki Ito Kazunori Yamada Mitsuhiro Kawano Yuya Kondo Kenichi Asano Masato Tanaka Marie Malissen Bernard Malissen Isao Matsumoto Takayuki Sumida |
| author_sort | Fumika Honda |
| collection | DOAJ |
| description | Abstract Background Our previous studies reveal that CCL18-CCR8 chemokine axis is upregulated in patients of immunoglobulin G4-related disease (IgG4-RD), suggesting that the CCL18–CCR8 axis is implicated in the etiology of IgG4-RD, although whether this axis has a potential as a therapeutic target remains unclear. Our purpose was to clarify the pathogenic roles and therapeutic potential of the murine CCL8 (analog of human CCL18)–CCR8 axis by using an animal model of IgG4-RD (LAT Y136F knockin mice; LAT mice). Methods We compared the infiltration of inflammatory cells and the fibrosis of the salivary glands of 6-week-old LAT mice and littermate mice. The expressions of Ccl8 and Ccr8 were also compared. Next, we investigated the therapeutic effects of intravenous administration of anti-CCL8 neutralizing antibody in LAT mice against inflammation and fibrosis of the salivary glands. We also investigated the effects of stimulation with recombinant mouse CCL8 on the collagen production in a mouse fibroblast cell line (NIH/3 T3) in vitro. Results When compared with the littermates, the LAT mice showed apparent infiltration of inflammatory cells and fibrosis in the salivary glands. The focus and fibrosis score in the salivary glands were significantly higher in the LAT mice than in the littermates. The expression levels of Ccl8 in the spleen and of Ccr8 in the salivary glands were significantly higher in the LAT mice than in the littermates. Anti-CCL8 antibody significantly improved the focus and fibrosis score in the salivary glands of the LAT mice. In vitro, stimulation with recombinant mouse CCL8 significantly increased the expression of collagen and ERK1/2 phosphorylation in NIH/3 T3. Conclusion We clarified the overexpression and therapeutic potential of the mouse CCL8–CCR8 axis in LAT mice, which could play a crucial role in fibrosis via ERK1/2 phosphorylation, as well as the chemotaxis of inflammatory cells. The human CCL18–CCR8 axis might be a novel therapeutic target for IgG4-RD. |
| first_indexed | 2024-12-22T11:03:19Z |
| format | Article |
| id | doaj.art-c11881d6588845c0bb000ce1e7a6f232 |
| institution | Directory Open Access Journal |
| issn | 1478-6362 |
| language | English |
| last_indexed | 2024-12-22T11:03:19Z |
| publishDate | 2021-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Arthritis Research & Therapy |
| spelling | doaj.art-c11881d6588845c0bb000ce1e7a6f2322022-12-21T18:28:25ZengBMCArthritis Research & Therapy1478-63622021-08-0123111210.1186/s13075-021-02597-6Pathogenic roles and therapeutic potential of the CCL8–CCR8 axis in a murine model of IgG4-related sialadenitisFumika Honda0Hiroto Tsuboi1Yuko Ono2Saori Abe3Hiroyuki Takahashi4Kiyoaki Ito5Kazunori Yamada6Mitsuhiro Kawano7Yuya Kondo8Kenichi Asano9Masato Tanaka10Marie Malissen11Bernard Malissen12Isao Matsumoto13Takayuki Sumida14Departments of Internal Medicine, Faculty of Medicine, University of TsukubaDepartments of Internal Medicine, Faculty of Medicine, University of TsukubaDepartments of Internal Medicine, Faculty of Medicine, University of TsukubaDepartments of Internal Medicine, Faculty of Medicine, University of TsukubaDepartments of Internal Medicine, Faculty of Medicine, University of TsukubaDepartment of Rheumatology, Graduate School of Medical Science, Kanazawa UniversityDepartment of Rheumatology, Graduate School of Medical Science, Kanazawa UniversityDepartment of Rheumatology, Graduate School of Medical Science, Kanazawa UniversityDepartments of Internal Medicine, Faculty of Medicine, University of TsukubaLaboratory of Immune Regulation, School of Life Science, Tokyo University of Pharmacy and Life ScienceLaboratory of Immune Regulation, School of Life Science, Tokyo University of Pharmacy and Life ScienceCentre d’Immunologie de Marseille-Luminy, Aix Marseille Université, INSERM, CNRSCentre d’Immunologie de Marseille-Luminy, Aix Marseille Université, INSERM, CNRSDepartments of Internal Medicine, Faculty of Medicine, University of TsukubaDepartments of Internal Medicine, Faculty of Medicine, University of TsukubaAbstract Background Our previous studies reveal that CCL18-CCR8 chemokine axis is upregulated in patients of immunoglobulin G4-related disease (IgG4-RD), suggesting that the CCL18–CCR8 axis is implicated in the etiology of IgG4-RD, although whether this axis has a potential as a therapeutic target remains unclear. Our purpose was to clarify the pathogenic roles and therapeutic potential of the murine CCL8 (analog of human CCL18)–CCR8 axis by using an animal model of IgG4-RD (LAT Y136F knockin mice; LAT mice). Methods We compared the infiltration of inflammatory cells and the fibrosis of the salivary glands of 6-week-old LAT mice and littermate mice. The expressions of Ccl8 and Ccr8 were also compared. Next, we investigated the therapeutic effects of intravenous administration of anti-CCL8 neutralizing antibody in LAT mice against inflammation and fibrosis of the salivary glands. We also investigated the effects of stimulation with recombinant mouse CCL8 on the collagen production in a mouse fibroblast cell line (NIH/3 T3) in vitro. Results When compared with the littermates, the LAT mice showed apparent infiltration of inflammatory cells and fibrosis in the salivary glands. The focus and fibrosis score in the salivary glands were significantly higher in the LAT mice than in the littermates. The expression levels of Ccl8 in the spleen and of Ccr8 in the salivary glands were significantly higher in the LAT mice than in the littermates. Anti-CCL8 antibody significantly improved the focus and fibrosis score in the salivary glands of the LAT mice. In vitro, stimulation with recombinant mouse CCL8 significantly increased the expression of collagen and ERK1/2 phosphorylation in NIH/3 T3. Conclusion We clarified the overexpression and therapeutic potential of the mouse CCL8–CCR8 axis in LAT mice, which could play a crucial role in fibrosis via ERK1/2 phosphorylation, as well as the chemotaxis of inflammatory cells. The human CCL18–CCR8 axis might be a novel therapeutic target for IgG4-RD.https://doi.org/10.1186/s13075-021-02597-6IgG4-related diseaseAnimal modelChemokineCCL18CCL8Fibrosis |
| spellingShingle | Fumika Honda Hiroto Tsuboi Yuko Ono Saori Abe Hiroyuki Takahashi Kiyoaki Ito Kazunori Yamada Mitsuhiro Kawano Yuya Kondo Kenichi Asano Masato Tanaka Marie Malissen Bernard Malissen Isao Matsumoto Takayuki Sumida Pathogenic roles and therapeutic potential of the CCL8–CCR8 axis in a murine model of IgG4-related sialadenitis Arthritis Research & Therapy IgG4-related disease Animal model Chemokine CCL18 CCL8 Fibrosis |
| title | Pathogenic roles and therapeutic potential of the CCL8–CCR8 axis in a murine model of IgG4-related sialadenitis |
| title_full | Pathogenic roles and therapeutic potential of the CCL8–CCR8 axis in a murine model of IgG4-related sialadenitis |
| title_fullStr | Pathogenic roles and therapeutic potential of the CCL8–CCR8 axis in a murine model of IgG4-related sialadenitis |
| title_full_unstemmed | Pathogenic roles and therapeutic potential of the CCL8–CCR8 axis in a murine model of IgG4-related sialadenitis |
| title_short | Pathogenic roles and therapeutic potential of the CCL8–CCR8 axis in a murine model of IgG4-related sialadenitis |
| title_sort | pathogenic roles and therapeutic potential of the ccl8 ccr8 axis in a murine model of igg4 related sialadenitis |
| topic | IgG4-related disease Animal model Chemokine CCL18 CCL8 Fibrosis |
| url | https://doi.org/10.1186/s13075-021-02597-6 |
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