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- Title
Mer tyrosine kinase as a possible link between resolution of inflammation and tissue fibrosis in IgG4-related disease.
- Authors
Rovati, Lucrezia; Kaneko, Naoki; Pedica, Federica; Monno, Antonella; Maehara, Takashi; Perugino, Cory; Lanzillotta, Marco; Pecetta, Simone; Stone, John H; Doglioni, Claudio; Manfredi, Angelo A; Pillai, Shiv; Della-Torre, Emanuel
- Abstract
Objectives IgG4-related disease (IgG4-RD) is a systemic fibro-inflammatory disorder characterized by a dysregulated resolution of inflammation and wound healing response that might develop after an apoptotic insult induced by cytotoxic T lymphocytes (CTLs). Mer receptor tyrosine kinase (MerTK) and its ligand, protein S (ProS1), have a pivotal role in the resolution of inflammation, being implicated in the clearance of apoptotic cells, quenching of the immune response and development of tissue fibrosis. In the present work we aimed to investigate a possible involvement of the MerTK signalling pathway in the pathogenesis of IgG4-RD and development of tissue fibrosis. Methods MerTK and ProS1 expression patterns in IgG4-RD lesions were evaluated by immunohistochemistry and immunofluorescence studies. Circulating MerTK + monocytes, soluble Mer and MerTK ligands were measured in the peripheral blood of IgG4-RD patients and healthy controls by flow cytometry and ELISA, respectively. Results MerTK was highly expressed by macrophages infiltrating IgG4-RD lesions. MerTK+ macrophages were more abundant in IgG4-RD than in Sjögren's syndrome and interacted with apoptotic cells and ProS1-expressing T and B lymphocytes. Moreover, they expressed the pro-fibrotic cytokine TGF-β and their numbers declined following rituximab-induced disease remission. Circulating MerTK+ monocytes, soluble Mer and MerTK ligands were not increased in the peripheral blood of patients with IgG4-RD. Conclusions The MerTK–ProS1 axis is activated in IgG4-RD lesions, possibly leading to persistent stimulation of processes involved in the resolution of inflammation and tissue fibrosis.
- Subjects
PROTEIN metabolism; LIGAND analysis; FLOW cytometry; TRANSFORMING growth factors-beta; RITUXIMAB; B cells; INFLAMMATION; PHOSPHOTRANSFERASES; IMMUNOHISTOCHEMISTRY; FIBROSIS; MACROPHAGES; CELLULAR signal transduction; ENZYME-linked immunosorbent assay; T cells; MONOCYTES; DISEASE remission
- Publication
Rheumatology, 2021, Vol 60, Issue 10, p4929
- ISSN
1462-0324
- Publication type
Article
- DOI
10.1093/rheumatology/keab096