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Activated M2 Macrophages Contribute to the Pathogenesis of IgG4‐Related Disease via Toll‐like Receptor 7/Interleukin‐33 Signaling
Author(s) -
Ishiguro Noriko,
Moriyama Masafumi,
Furusho Katsuhiro,
Furukawa Sachiko,
Shibata Takuma,
Murakami Yusuke,
Chinju Akira,
Haque A. S. M. Rafiul,
Gion Yuka,
Ohta Miho,
Maehara Takashi,
Tanaka Akihiko,
Yamauchi Masaki,
Sakamoto Mizuki,
Mochizuki Keita,
Ono Yuko,
Hayashida JunNosuke,
Sato Yasuharu,
Kiyoshima Tamotsu,
Yamamoto Hidetaka,
Miyake Kensuke,
Nakamura Seiji
Publication year - 2020
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.41052
Subject(s) - toll like receptor , pathogenesis , tlr2 , receptor , sialadenitis , cytokine , immunology , biology , tlr4 , immune system , medicine , pathology , salivary gland , innate immune system
Objective IgG4‐related disease (IgG4‐ RD ) is a unique inflammatory disorder in which Th2 cytokines promote IgG4 production. In addition, recent studies have implicated the Toll‐like receptor ( TLR ) pathway. This study was undertaken to examine the expression of TLR s in salivary glands ( SG s) from patients with IgG4‐ RD . Methods SG s from 15 patients with IgG4‐ RD , 15 patients with Sjögren's syndrome ( SS ), 10 patients with chronic sialadenitis, and 10 healthy controls were examined histologically. TLR family gene expression ( TLR ‐1 through TLR ‐10) was analyzed by DNA microarray in the submandibular glands ( SMG s). Up‐regulation of TLR s was confirmed in SG s from patients with IgG4‐ RD . Finally, the phenotype of human TLR ‐7 (hu TLR ‐7)–transgenic C57 BL /6 mice was assessed before and after stimulation with TLR agonist. Results In patients with IgG4‐ RD , TLR ‐4, TLR ‐7, TLR ‐8, and TLR ‐9 were overexpressed. Polymerase chain reaction validated the up‐regulation of TLR ‐7 in IgG4‐ RD compared with the other groups. Immunohistochemical analysis confirmed strong infiltration of TLR ‐7–positive cells in the SG s of patients with IgG4‐ RD . Double immunohistochemical staining showed that TLR ‐7 expression colocalized with CD 163+ M2 macrophages. After in vitro stimulation with a TLR ‐7 agonist, CD 163+ M2 macrophages produced higher levels of interleukin‐33 ( IL ‐33), which is a Th2‐activating cytokine. In hu TLR ‐7–transgenic mice, the focus and fibrosis scores in SMG s, pancreas, and lungs were significantly higher than those in wild‐type mice ( P < 0.05). Moreover, the concentration of serum IgG, IgG1, and IL ‐33 in hu TLR ‐7–transgenic mice was distinctly increased upon stimulation with a TLR ‐7 agonist ( P < 0.05). Conclusion TLR ‐7–expressing M2 macrophages may promote the activation of Th2 immune responses via IL ‐33 secretion in IgG4‐ RD .