1. Pathogenic roles and therapeutic potential of the CCL8-CCR8 axis in a murine model of IgG4-related sialadenitis
- Author
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Kazunori Yamada, Isao Matsumoto, Yuko Ono, Yuya Kondo, Takayuki Sumida, Masato Tanaka, Kenichi Asano, Marie Malissen, Bernard Malissen, Saori Abe, Fumika Honda, Hiroyuki Takahashi, Hiroto Tsuboi, Kiyoaki Ito, Mitsuhiro Kawano, Université de Tsukuba = University of Tsukuba, Kanazawa University (KU), Tokyo University of Pharmacy and Life Sciences (TUPLS), Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Centre d'Immunophénomique (CIPHE), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and DUMENIL, Anita
- Subjects
Chemokine ,[SDV]Life Sciences [q-bio] ,Inflammation ,Spleen ,Diseases of the musculoskeletal system ,CCR8 ,CCL8 ,Receptors, CCR8 ,Salivary Glands ,Sialadenitis ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Fibrosis ,CCL18 ,Medicine ,Animals ,Chemokine CCL8 ,Humans ,Animal model ,IgG4-related disease ,030304 developmental biology ,0303 health sciences ,biology ,business.industry ,medicine.disease ,3. Good health ,[SDV] Life Sciences [q-bio] ,Disease Models, Animal ,medicine.anatomical_structure ,RC925-935 ,Chemokines, CC ,Immunoglobulin G ,Cancer research ,biology.protein ,Immunoglobulin G4-Related Disease ,medicine.symptom ,business ,030215 immunology ,Research Article - 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.
- Published
- 2021