Activated M2 Macrophages Contribute to the Pathogenesis of IgG4‐Related Disease via Toll‐like Receptor 7/Interleukin‐33 Signaling
Open accessAbstract
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 .
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TLR9 is expressed in various immune cells, such as macrophages, NK cells, B lymphocytes and plasmacytoid dendritic cells.
“Toll-like receptor 9 (TLR9) is expressed in various immune cells, such as macrophages, NK cells, B lymphocytes and plasmacytoid dendritic cells [146, 147].”
From Resistance to anti-EGFR therapies in metastatic colorectal cancer: underlying mechanisms and reversal strategies (2021) · cites this paper as [147]
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- Authors
- Ishiguro, N., Moriyama, M., Furusho, K., Furukawa, S., Shibata, T., Murakami, Y., Chinju, A., Haque, A. S. M. R., Gion, Y., Ohta, M., Maehara, T., Tanaka, A., Yamauchi, M., Sakamoto, M., Mochizuki, K., Ono, Y., Hayashida, J., Sato, Y., Kiyoshima, T., Yamamoto, H., Miyake, K., & Nakamura, S.
- Affiliations
- Kyushu University (JP)
- The University of Tokyo (JP)
- Okayama University (JP)
- Kyushu University Hospital (JP)
- Corresponding author
- Moriyama, Masafumi
- ORCID
- Venue
- Arthritis & Rheumatology
- Publisher
- Wiley
- Published
- 2019-11-29
- Volume
- 72
- Issue
- 1
- Pages
- 166-178
- ISSN
- 2326-5191 (ISSN-L)
- 2326-5205
- PMC
- PMC6972995
- OpenAlex
- W2963580022
- Cited by
- 86
- References
- 50
- Citations by year
- 2026: 8 · 2025: 15 · 2024: 13 · 2023: 14 · 2022: 7 · 2021: 19 · 2020: 10
- FWCI
- 6.82
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Arthritis & Rheumatology (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (15H06491, 17H01603, 17H04671, 26293430)
- Japan Agency for Medical Research and Development (17ek0109226h0001)
- Topics
- Health Sciences › Medicine › Rheumatology › IgG4-Related and Inflammatory Diseases
- Health Sciences › Medicine › Physiology › Salivary Gland Disorders and Functions
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- TLR7, M2 macrophages, IL-33, Th2 immune response, salivary glands, CD163, fibrosis, Sjögren's syndrome, chronic sialadenitis, TLR gene expression, TLR agonists
- MeSH terms
- Interleukin-33, Immunoglobulin G4-Related Disease, Adult, Aged, Animals, Female, Humans, Macrophages, Male, Mice, Transgenic, Middle Aged, Sialadenitis, Sjogren's Syndrome, Submandibular Gland, Signal Transduction, Up-Regulation, Case-Control Studies, Th2 Cells, Toll-Like Receptor 4, Toll-Like Receptor 7, Toll-Like Receptor 8, Toll-Like Receptor 9
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