IL-37 Represses the Autoimmunity in Myasthenia Gravis via Directly Targeting Follicular Th and B Cells

Liu, Zhuo; Zhu, Liwen; Lù, Zhongwen; Chen, Huiping; Fan, Lizhen; Xue, Qun; Shi, Jian-Quan; Li, Meiying; Li, Hui; Gong, Jie; Shi, Jingping; Wang, Tao; Jiang, Meiling; Cao, Runjing; Meng, Hailan; Wang, Chenhui; Xu, Yun; Zhang, Cunjin

doi:10.4049/jimmunol.1901176

Cited by 17 publications

(13 citation statements)

References 65 publications

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“…Tfh and B cells in MG patients have high expression of the IL-37-receptor SIGIRR. IL-37 in MG patients is mainly synthesized by CD4 + T cells without overlapping with Th1, Th17, and Tfh subsets (76). In addition, regulatory IL-37 + T cells rarely express Foxp3 and CD25, while IL-4 is highly expressed (76).…”

Section: Myasthenia Gravismentioning

confidence: 99%

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Current Understanding of IL-37 in Human Health and Disease

Tao

2021

Front. Immunol.

112

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IL-37 is a recently discovered cytokine in the IL-1 family exerting broad protective effects on inflammatory diseases, autoimmune diseases, and cancer. Immune and non-immune cells produce the IL-37 precursor upon pro-inflammatory stimuli. Intracellularly, caspase-1 cleaves and activates IL-37, and its mature form binds to Smad3; this complex translocates into the nucleus where it suppresses cytokine production, consequently reducing inflammation. Extracellularly, IL-37 forms a complex with IL-18Rα and IL-1R8 (formerly TIR8 or SIGIRR) that transduces anti-inflammatory signals by the suppression of NF-κB and MAPK and the activation of Mer-PTEN-DOK pathways. During inflammation, IL-37 suppresses the expression of several pro-inflammatory cytokine in favor to the expression of the anti-inflammatory ones by the regulation of macrophage polarization, lipid metabolism, inflammasome function, TSLP synthesis and miRNAs function. Moreover, IL-37 not only regulates the innate and acquired immunity, but also improves aging-associated immunosenescence. Furthermore, IL-37 exerts an inhibitory effect on tumor angiogenesis and metastasis, and progression. Finally, IL-37 may have a potential ability to reduce excessive inflammation since it is aberrantly expressed in patients with inflammatory diseases, autoimmune diseases, and cancer, thus, it may be used as a marker for different types of diseases. Therefore, this review provides an updated view of the role of IL-37 in human health and disease, and discusses the potential of IL-37 as a therapeutic target and biomarker in inflammatory diseases, autoimmune diseases, and cancer.

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Section: Myasthenia Gravismentioning

confidence: 99%

“…Patients with MG possess a much lower IL-37 level in the serum and PBMCs than HCs, which is associated with severer disease (quantitative MG score), and higher follicular Th (Tfh)/Tfh17 and B cell number (76). Tfh and B cells in MG patients have high expression of the IL-37-receptor SIGIRR.…”

Section: Myasthenia Gravismentioning

confidence: 99%

Current Understanding of IL-37 in Human Health and Disease

Tao

2021

Front. Immunol.

112

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“…In addition to CXCR5, CCR7, PSGL1, and S1P receptors that are involved in cell migration, SLAM family receptors and integrins are also involved in regulating Tfh cell functions [32]. In addition, other regulators, including ICOSL [222], Ascl2 [229], Itch [230], VHL [231], IL-37 [232], HIF-1α [233], COX-1 [234], Th-POK [235], and Tox2 [236] are also found to be important for Tfh cell differentiation and functions. Tfh cells provide help to GC B cells in two aspects: one is to promote GC B cell maturation, and the other is to promote antibody production.…”

Section: Tfh Cellsmentioning

confidence: 99%

CD4 T Helper Cell Subsets and Related Human Immunological Disorders

Zhu

2020

IJMS

222

138

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The immune system plays a critical role in protecting hosts from the invasion of organisms. CD4 T cells, as a key component of the immune system, are central in orchestrating adaptive immune responses. After decades of investigation, five major CD4 T helper cell (Th) subsets have been identified: Th1, Th2, Th17, Treg (T regulatory), and Tfh (follicular T helper) cells. Th1 cells, defined by the expression of lineage cytokine interferon (IFN)-γ and the master transcription factor T-bet, participate in type 1 immune responses to intracellular pathogens such as mycobacterial species and viruses; Th2 cells, defined by the expression of lineage cytokines interleukin (IL)-4/IL-5/IL-13 and the master transcription factor GAΤA3, participate in type 2 immune responses to larger extracellular pathogens such as helminths; Th17 cells, defined by the expression of lineage cytokines IL-17/IL-22 and the master transcription factor RORγt, participate in type 3 immune responses to extracellular pathogens including some bacteria and fungi; Tfh cells, by producing IL-21 and expressing Bcl6, help B cells produce corresponding antibodies; whereas Foxp3-expressing Treg cells, unlike Th1/Th2/Th17/Tfh exerting their effector functions, regulate immune responses to maintain immune cell homeostasis and prevent immunopathology. Interestingly, innate lymphoid cells (ILCs) have been found to mimic the functions of three major effector CD4 T helper subsets (Th1, Th2, and Th17) and thus can also be divided into three major subsets: ILC1s, ILC2s, and ILC3s. In this review, we will discuss the differentiation and functions of each CD4 T helper cell subset in the context of ILCs and human diseases associated with the dysregulation of these lymphocyte subsets particularly caused by monogenic mutations.

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“…Therefore, it is understandable that LPS could activate phosphorylation of the STAT3 pathway through IL-6 indirectly. Previous studies suggested that IL-37 could inhibit the activation of the NF- κ B and IL-6/STAT3 signaling pathway and suppressed the occurrence of the inflammatory response in Myasthenia Gravis (MG) by affecting Tfh and B cells, and in lung cancer by affecting A549 cells [ 46 , 51 ]. However, the anti-inflammatory effect of IL-37 via the NF- κ B and IL-6/STAT3 pathway in preterm birth remains elusive.…”

Section: Discussionmentioning

confidence: 99%

IL-37 Exerts Anti-Inflammatory Effects in Fetal Membranes of Spontaneous Preterm Birth via the NF-κB and IL-6/STAT3 Signaling Pathway

Wang

Liu

Huang

et al. 2020

Mediators of Inflammation

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Spontaneous preterm birth (sPTB), defined as delivery before 37 weeks of gestation, is thought to be a multifactorial syndrome. However, the inflammatory imbalance at the maternal-fetal interface promotes excessive secretion of inflammatory factors and induces apoptosis and degradation of the extracellular matrix (ECM), which can subsequently lead to preterm birth. As an anti-inflammatory molecule in the IL-1 family, interleukin-37 (IL-37) mainly plays an inhibiting role in a variety of inflammatory diseases. However, as a typical inflammatory disease, no previous studies have been carried out to explore the role of IL-37 in sPTB. In this study, a series of molecular biological experiments were performed in clinical samples and human amniotic epithelial cell line (Wistar Institute Susan Hayflick (WISH)) to investigate the deficiency role of IL-37 and the potential mechanism. Firstly, the results indicated that the expression of IL-37 in human peripheral plasma and fetal membranes was significantly decreased in the sPTB group. Afterward, it is proved that IL-37 could significantly suppress the production of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in WISH cells. Simultaneously, once silence IL-37, LPS-induced apoptosis and activity of matrix metalloproteinases (MMPs) 2 and 9 were significantly increased. In addition, the western blot data showed that IL-37 performed its biological effects by inhibiting the NF-κB and IL-6/STAT3 pathway. In conclusion, our results suggest that IL-37 limits excessive inflammation and subsequently inhibits ECM remodeling and apoptosis through the NF-κB and IL-6/STAT3 signaling pathway in the fetal membranes.

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IL-37 Represses the Autoimmunity in Myasthenia Gravis via Directly Targeting Follicular Th and B Cells

Cited by 17 publications

References 65 publications

Current Understanding of IL-37 in Human Health and Disease

Current Understanding of IL-37 in Human Health and Disease

CD4 T Helper Cell Subsets and Related Human Immunological Disorders

IL-37 Exerts Anti-Inflammatory Effects in Fetal Membranes of Spontaneous Preterm Birth via the NF-κB and IL-6/STAT3 Signaling Pathway

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