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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 3

The protective function of CTRP4 is T cell intrinsic for IL-6 signaling.

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The protective function of CTRP4 is T cell intrinsic for IL-6 signaling....
(A) Mean clinical scores of chimeric mice generated by (i) transfer of WT bone marrow cells into irradiated WT and Ctrp4–/– recipient mice or (ii) transfer of Ctrp4–/– bone marrow cells into irradiated WT and Ctrp4–/– recipient mice (each n = 6–8) following MOG35–55 immunization. Statistical significance was determined using 2-way repeated measures ANOVA and Holm-Šidák post hoc test. (B) Representative H&E staining of spinal cord sections harvested from chimeric WT and Ctrp4–/– mice showed inflammatory cell infiltration and demyelination at day 18 after immunization. Scale bars: 200 μm. (C) Flow-cytometric analysis of absolute cell numbers of CNS-infiltrating T cells (CD45+CD3+CD4+ T and CD45+CD3+CD8+ T) and B cells (CD45+CD3–CD19+) at 18 days after immunization. (D) Flow-cytometric analysis of absolute numbers of different CNS-infiltrating myeloid cells including monocytes (CD45+CD11b+Ly6C+), neutrophils (CD45+CD11b+Ly6G+), and DCs (CD45+CD11c+MHCII+) at 18 days after immunization. (E) Flow-cytometric analysis of absolute numbers of Th1 cells (IFN-γ+), Th17 cells (IL-17A+), and Tregs (CD25+Foxp3+) of CD4+ T cells infiltrated to the CNS harvested at 18 days after immunization. (F) Mean clinical scores of CTRP4fl/fl and CD4-cre CTRP4fl/fl mice were monitored after MOG immunization. Data are representative of 3 independent experiments. Statistical significance was determined using 2-way repeated-measures ANOVA. (G) H&E staining (left) and LFB staining (right) of spinal cord sections harvested from CTRP4fl/fl and CD4-cre CTRP4fl/fl mice at day 18 after EAE induction. Data are represented as mean ± SEM and are from 1 of 3 independent experiments with similar results. One-way ANOVA with Tukey’s post test (C–E). *P < 0.05; **P < 0.01; ***P < 0.0001.

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