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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 7

Mechanism underlying the inhibition of Th17 cell differentiation by CTRP4.

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Mechanism underlying the inhibition of Th17 cell differentiation by CTRP...
(A and B) Proliferative response of Ba/F3–gp130–IL-6R cells cultured for 2 days in the presence of exogenous rhCTRP4 (100 ng/mL), OSM (100 ng/mL), IL-6 (10 ng/mL), IL-3 (10 ng/mL), rhCTRP4 plus IL-6, or OSM plus rhCTRP4, or left untreated (A). (B) Proliferative response of Ba/F3-gp130 cells cultured for 2 days with OSM (100 ng/mL), IL-6 (10 ng/mL), rhCTRP4 (100 ng/mL), hyper–IL-6 (10 ng/mL), a combination of IL-6 (10 ng/mL) and IL-6R (10 ng/mL), a combination of IL-6 and IL-6R plus rhCTRP4, hyper–IL-6 plus rhCTRP4, or IL-3 (10 ng/mL). The proliferation in indicated culture conditions was determined by the colorimetric CCK8 assay. Results are shown as RLUs and normalized to the growth of cells cultured in medium. (C) Purified WT CD4+ cells were activated with hyper–IL-6 (10 ng/mL) prior to treatment with rhCTRP4 for 1 hour or without treatment as control. Western blot was performed to analyze the activation of STAT3. (D) Naive CD4+ T cells were differentiated toward Th17 cells with TGF-β plus the combination of IL-6 (10 ng/mL) and IL-6R (10 ng/mL) in the presence or absence of rhCTRP4 (100 ng/mL) or differentiated toward Th17 cells with TGF-β and hyper–IL-6 (10 ng/mL) in the presence or absence of rhCTRP4 (100 ng/mL). Data are represented as mean ± SEM and are from 1 of 3 independent experiments with similar results. (A, B, and D) Statistical significance was determined using 1-way ANOVA with Tukey’s post test.**P < 0.01.

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