Interleukin-33 produced by M2 macrophages and other immune cells contributes to Th2 immune reaction of IgG4-related disease

Furukawa, Soichi; Moriyama, Masafumi; Miyake, Kensuke; Nakashima, Hitoshi; Tanaka, Akihiko; Mitsui, Takashi; Iizuka‐Koga, Mana; Tsuboi, Hiroto; Hayashida, Jun Nosuke; Ishiguro, Nozomu; Yamauchi, Masaki; Sumida, Takayuki; Nakamura, Seiji

doi:10.1038/srep42413

Cited by 104 publications

(77 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Relationship between TLR-7 and IL-33 expression in the SGs. As mentioned above, our recent data indicate that M2 macrophages might contribute to aberrant activation of Th2 immune responses and fibrosis via production of IL-33 (15,16). IL-33 is a recently described cytokine and directly stimulates ST2-expressing immune cells, including Th2 cells, mast cells, eosinophils, and basophils, to secrete Th2 cytokines (35).…”

Section: Identification Of Tlr-7-expressing Cells In the Smgs And Normentioning

confidence: 82%

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

Ishiguro

Moriyama

Furusho

et al. 2019

Arthritis & Rheumatology

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Identification Of Tlr-7-expressing Cells In the Smgs And Normentioning

confidence: 82%

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

Ishiguro

Moriyama

Furusho

et al. 2019

Arthritis & Rheumatology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Acting via the ST2 receptor on a variety of cells, including Th2 and group 2 innate lymphoid cells, it induces Th2 cytokine responses and other proinflammatory responses (23). Indeed, recent studies by Furukawa et al (34) implicate the role of IL-33 as an inducer of Th2 responses in IgG4-RD. However, it also activates Th1 responses in cytotoxic antiviral T cells (35).…”

Section: Discussionmentioning

confidence: 99%

Chronic Fibro-Inflammatory Responses in Autoimmune Pancreatitis Depend on IFN-α and IL-33 Produced by Plasmacytoid Dendritic Cells

Watanabe

Yamashita

Arai

et al. 2017

The Journal of Immunology

View full text Add to dashboard Cite

In previous studies, we found that human IgG4-related autoimmune pancreatitis (AIP) and murine AIP are driven by activation of plasmacytoid dendritic cells (pDCs) producing IFN-α. In the present studies we examined additional roles of pDC-related mechanisms in AIP pathogenesis, particularly those responsible for induction of fibrosis. We found that in murine AIP (MRL/Mp mice treated with polyinosinic-polycytidylic acid) not only the pancreatic infiltration of immune cells but also the development of fibrosis were markedly reduced by the depletion of pDCs or blockade of type I IFN signaling; moreover, such treatment was accompanied by a marked reduction of pancreatic expression of IL-33. Conversely, polyinosinic-polycytidylic acid-induced inflamed pancreatic tissue in murine AIP exhibited increased expression of type I IFNs and IL-33 (and downstream IL-33 cytokines such as IL-13 and TGF-β1). pDCs stimulated by type I IFN were the source of the IL-33 because purified populations of these cells isolated from the inflamed pancreas produced a large amount of IL-33 upon activation by TLR9 ligands, and such production was abrogated by the neutralization of type I IFN. The role of IL-33 in murine AIP pathogenesis was surprisingly important because blockade of IL-33 signaling by anti-ST2 Ab attenuated both pancreatic inflammation and accompanying fibrosis. Finally, whereas patients with both conventional pancreatitis and IgG4-related AIP exhibited increased numbers of acinar cells expressing IL-33, only the latter also exhibited pDCs producing this cytokine. These data thus suggest that pDCs producing IFN-α and IL-33 play a pivotal role in the chronic fibro-inflammatory responses underlying murine AIP and human IgG4-related AIP.

show abstract

“…Increase of CD163þ M2 macrophages and the amount of fibrosis in biopsy specimens are reported in patients with IgG4-RD. In addition, abundant interleukin-33 (IL-33) produced by macrophages, dendritic cells and damaged epithelial cells was detected in salivary glands, which might activate Th2 immune responses in patients with IgG4-RD [21]. Alternatively, macrophages from patients with IgG4-RD induce IgG4-production by BAFF released from B cells upon stimulation of Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain receptors (NOD)-like receptors [22].…”

Section: Innate Immunitymentioning

confidence: 99%

The front line of research into immunoglobin G4-related disease - Do autoantibodies cause immunoglobin G4-related disease?

Umehara

Okazaki

Kawano

et al. 2019

Modern Rheumatology

View full text Add to dashboard Cite

IgG4-related disease (IgG4-RD) is a novel clinical disease entity characterized by elevated serum IgG4 concentration and tumefaction or tissue infiltration by IgG4-positive plasma cells. Although IgG4-RD is attracting strong attention as a new clinical entity, the pathogenesis of IgG4-RD and the roles of IgG4 are still unknown. Recently, self-antigens including Laminin 511 E8, Galectin-3 and Annexin A11, have been reported from one to the next as autoantigens which may be involved in the pathogenesis of IgG4-RD. In this review, we describe up-to-date information on the research of this emerging disease entity. Moreover, we discuss the pathogenesis of IgG4-RD by focusing on recent reports concerning autoantibodies. ARTICLE HISTORY

show abstract

Interleukin-33 produced by M2 macrophages and other immune cells contributes to Th2 immune reaction of IgG4-related disease

Cited by 104 publications

References 47 publications

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

Chronic Fibro-Inflammatory Responses in Autoimmune Pancreatitis Depend on IFN-α and IL-33 Produced by Plasmacytoid Dendritic Cells

The front line of research into immunoglobin G4-related disease - Do autoantibodies cause immunoglobin G4-related disease?

Contact Info

Product

Resources

About