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CTRP4/interleukin-6 receptor signaling ameliorates autoimmune encephalomyelitis by suppressing Th17 cell differentiation
Lulu Cao, … , Xiaoxin Zhu, Lu Wang
Lulu Cao, … , Xiaoxin Zhu, Lu Wang
Published November 28, 2023
Citation Information: J Clin Invest. 2024;134(4):e168384. https://doi.org/10.1172/JCI168384.
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Research Article Autoimmunity

CTRP4/interleukin-6 receptor signaling ameliorates autoimmune encephalomyelitis by suppressing Th17 cell differentiation

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Abstract

C1q/TNF-related protein 4 (CTRP4) is generally thought to be released extracellularly and plays a critical role in energy metabolism and protecting against sepsis. However, its physiological functions in autoimmune diseases have not been thoroughly explored. In this study, we demonstrate that Th17 cell–associated experimental autoimmune encephalomyelitis was greatly exacerbated in Ctrp4–/– mice compared with WT mice due to increased Th17 cell infiltration. The absence of Ctrp4 promoted the differentiation of naive CD4+ T cells into Th17 cells in vitro. Mechanistically, CTRP4 interfered with the interaction between IL-6 and the IL-6 receptor (IL-6R) by directly competing to bind with IL-6R, leading to suppression of IL-6–induced activation of the STAT3 pathway. Furthermore, the administration of recombinant CTRP4 protein ameliorated disease symptoms. In conclusion, our results indicate that CTRP4, as an endogenous regulator of the IL-6 receptor–signaling pathway, may be a potential therapeutic intervention for Th17-driven autoimmune diseases.

Authors

Lulu Cao, Jinhai Deng, Wei Chen, Minwei He, Ning Zhao, He Huang, Lu Ling, Qi Li, Xiaoxin Zhu, Lu Wang

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Figure 9

IL-6 signaling blockade abrogates the protective effects of CTRP4 in EAE.

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IL-6 signaling blockade abrogates the protective effects of CTRP4 in EAE...
(A) WT mice were intraperitoneally injected with anti–IL-6R or control IgG on immunization days –1, 3, 7, 11, and 15(n = 5 mice/group). After EAE induction, mice were treated with rhCTRP4 or BSA daily from day 0 to day 27. Mean clinical scores show progression of disease. (B) CNS monocytes were harvested on day 18 and quantified as absolute cell numbers of indicated CNS-infiltrating cell populations gated on CD45+. (C) CNS monocytes were harvested on day 18 and quantified as absolute numbers of CD4+IFN-γ+, CD4+IL-17A+, and CD4+IL-17A+IFN-γ+ in CNS after stimulating with PMA and inomycin with GolgiPlug for 5 hours. (D) Ctrp4–/– and WT mice subjected to MOG-induced EAE were treated with selective STAT3 inhibitor S3I-201 (10 mg/kg/d dissolved in 20%DMSO/80% corn oil). Control mice were injected with equal volumes of vehicle. Each group was monitored and scored daily (n = 7/group). (E) Representative images of H&E staining and LFB staining of spinal cord sections show inflammatory cell infiltration and demyelination, respectively. Scale bar: 200 μm. Data are represented as mean ± SEM and were analyzed by 1-way ANOVA with Tukey’s post test (B and C). Two-way repeated measures ANOVA and Holm-Šidák post hoc test (A and D).*P < 0.05; **P < 0.01.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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