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

Noriko Ishiguro, Masafumi Moriyama, Katsuhiro Furusho, Sachiko Furukawa, Takuma Shibata, Yusuke Murakami, Akira Chinju, A. S.M.Rafiul Haque, Yuka Gion, Miho Ohta, Takashi Maehara, Akihiko Tanaka, Masaki Yamauchi, Mizuki Sakamoto, Keita Mochizuki, Yuko Ono, Jun Nosuke Hayashida, Yasuharu Sato, Tamotsu Kiyoshima, Hidetaka YamamotoKensuke Miyake, Seiji Nakamura

Research output: Contribution to journalArticle

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.

Original languageEnglish
JournalArthritis and Rheumatology
DOIs
Publication statusAccepted/In press - Jan 1 2019

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Toll-Like Receptor 7
Immunoglobulin G
Macrophages
Toll-Like Receptors
Salivary Glands
Submandibular Gland
Toll-Like Receptor 10
Toll-Like Receptor 8
Interleukin-33
Up-Regulation
Toll-Like Receptor 1
Toll-Like Receptor 9
Sialadenitis
Cytokines
Toll-Like Receptor 4
Oligonucleotide Array Sequence Analysis
Inbred C57BL Mouse
Transgenic Mice
Pancreas

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology

Cite this

Activated M2 Macrophages Contribute to the Pathogenesis of IgG4-Related Disease via Toll-Like Receptor 7/Interleukin-33 Signaling. / 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, Jun Nosuke; Sato, Yasuharu; Kiyoshima, Tamotsu; Yamamoto, Hidetaka; Miyake, Kensuke; Nakamura, Seiji.

In: Arthritis and Rheumatology, 01.01.2019.

Research output: Contribution to journalArticle

Ishiguro, N, Moriyama, M, Furusho, K, Furukawa, S, Shibata, T, Murakami, Y, Chinju, A, Haque, ASMR, Gion, Y, Ohta, M, Maehara, T, Tanaka, A, Yamauchi, M, Sakamoto, M, Mochizuki, K, Ono, Y, Hayashida, JN, Sato, Y, Kiyoshima, T, Yamamoto, H, Miyake, K & Nakamura, S 2019, 'Activated M2 Macrophages Contribute to the Pathogenesis of IgG4-Related Disease via Toll-Like Receptor 7/Interleukin-33 Signaling', Arthritis and Rheumatology. https://doi.org/10.1002/art.41052
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, Jun Nosuke ; Sato, Yasuharu ; Kiyoshima, Tamotsu ; Yamamoto, Hidetaka ; Miyake, Kensuke ; Nakamura, Seiji. / Activated M2 Macrophages Contribute to the Pathogenesis of IgG4-Related Disease via Toll-Like Receptor 7/Interleukin-33 Signaling. In: Arthritis and Rheumatology. 2019.
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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 Sj{\"o}gren'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.",
author = "Noriko Ishiguro and Masafumi Moriyama and Katsuhiro Furusho and Sachiko Furukawa and Takuma Shibata and Yusuke Murakami and Akira Chinju and Haque, {A. S.M.Rafiul} and Yuka Gion and Miho Ohta and Takashi Maehara and Akihiko Tanaka and Masaki Yamauchi and Mizuki Sakamoto and Keita Mochizuki and Yuko Ono and Hayashida, {Jun Nosuke} and Yasuharu Sato and Tamotsu Kiyoshima and Hidetaka Yamamoto and Kensuke Miyake and Seiji Nakamura",
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T1 - Activated M2 Macrophages Contribute to the Pathogenesis of IgG4-Related Disease via Toll-Like Receptor 7/Interleukin-33 Signaling

AU - Ishiguro, Noriko

AU - Moriyama, Masafumi

AU - Furusho, Katsuhiro

AU - Furukawa, Sachiko

AU - Shibata, Takuma

AU - Murakami, Yusuke

AU - Chinju, Akira

AU - Haque, A. S.M.Rafiul

AU - Gion, Yuka

AU - Ohta, Miho

AU - Maehara, Takashi

AU - Tanaka, Akihiko

AU - Yamauchi, Masaki

AU - Sakamoto, Mizuki

AU - Mochizuki, Keita

AU - Ono, Yuko

AU - Hayashida, Jun Nosuke

AU - Sato, Yasuharu

AU - Kiyoshima, Tamotsu

AU - Yamamoto, Hidetaka

AU - Miyake, Kensuke

AU - Nakamura, Seiji

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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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