2. Academic Validation
  3. Activated M2 Macrophages Contribute to the Pathogenesis of IgG4-Related Disease via Toll-like Receptor 7/Interleukin-33 Signaling

Activated M2 Macrophages Contribute to the Pathogenesis of IgG4-Related Disease via Toll-like Receptor 7/Interleukin-33 Signaling

  • Arthritis Rheumatol. 2020 Jan;72(1):166-178. doi: 10.1002/art.41052.
Noriko Ishiguro 1,  Masafumi Moriyama 1,  Katsuhiro Furusho 2,  Sachiko Furukawa 1,  Takuma Shibata 3,  Yusuke Murakami 3,  Akira Chinju 1,  A S M Rafiul Haque 1,  Yuka Gion 4,  Miho Ohta 1,  Takashi Maehara 1,  Akihiko Tanaka 1,  Masaki Yamauchi 1,  Mizuki Sakamoto 1,  Keita Mochizuki 1,  Yuko Ono 1,  Jun-Nosuke Hayashida 1,  Yasuharu Sato 4,  Tamotsu Kiyoshima 1,  Hidetaka Yamamoto 5,  Kensuke Miyake 3,  Seiji Nakamura 1
Affiliations

Affiliations

  • 1 Kyushu University, Fukuoka, Japan.
  • 2 Kyushu University, Fukuoka, Japan, and University of Tokyo, Tokyo, Japan.
  • 3 University of Tokyo, Tokyo, Japan.
  • 4 Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
  • 5 Kyushu University Hospital, Fukuoka, Japan.
PMID: 31339007 DOI: 10.1002/art.41052
Abstract

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 TLRs in salivary glands (SGs) from patients with IgG4-RD.

Methods: SGs 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 (SMGs). Up-regulation of TLRs was confirmed in SGs from patients with IgG4-RD. Finally, the phenotype of human TLR-7 (huTLR-7)-transgenic C57BL/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 SGs of patients with IgG4-RD. Double immunohistochemical staining showed that TLR-7 expression colocalized with CD163+ M2 macrophages. After in vitro stimulation with a TLR-7 agonist, CD163+ M2 macrophages produced higher levels of interleukin-33 (IL-33), which is a Th2-activating cytokine. In huTLR-7-transgenic mice, the focus and fibrosis scores in SMGs, 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 huTLR-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.

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