A&R: IL-34重编程糖酵解和破骨性类风湿性关节炎巨噬细胞

2021-12-03 MedSci原创 MedSci原创

IL-34是一种新型内源性因子，可重塑高代谢M34巨噬细胞并促进其与T效应细胞的交叉调节从而引起RA的炎症性骨破坏。

在类风湿性关节炎 (RA) 中，血清白介素34 (IL-34)水平升高与疾病严重程度增加有关。IL-34与2种受体结合，即巨噬细胞集落刺激因子受体(M-CSFR)和Syndecan 1，它们在RA巨噬细胞中共表达。IL-34和syndecan 1的表达在RA滑膜中显著升高，但它们的作用机制还不清楚。本研究旨在研究IL-34在RA中的作用机制。

为了表征IL-34在免疫代谢中的重要性，使用RA和临床前模型在关节巨噬细胞、成纤维细胞和T效应细胞中阐明其作用机制。有趣的是，syndecan 1激活了IL-34诱导的M-CSFR磷酸化，并将RA幼稚细胞重编程为独特的CD14+CD86+GLUT1+M34巨噬细胞，这些巨噬细胞高表达IL-1β、CXCL8和CCL2。在鼠M34巨噬细胞中，炎症表型伴随着增强的糖酵解活性，表现为GLUT1、c-Myc和缺氧诱导因子1α(HIF-1α)的转录上调以及丙酮酸和L-乳酸分泌增加。IL-34的局部表达通过升高糖酵解F4/80阳性、诱导型一氧化氮合酶 (iNOS) 阳性巨噬细胞群，进而吸引成纤维细胞和极化的Th1/Th17细胞引起关节炎。鼠M34巨噬细胞和 Th1/Th17细胞之间的互相影响扩大了炎症和代谢表型，使IL-34致病性增加。因此，与野生型小鼠相比，RAG-/-小鼠中IL-34引发的关节炎症得到缓解。Syndecan 1缺乏通过干扰关节糖酵解M34巨噬细胞和破骨细胞重塑来减轻IL-34诱导的关节炎。同样，2-脱氧-d-葡萄糖对糖酵解的抑制逆转了IL-34通过HIF-1α和c-Myc诱导引发的关节肿胀和代谢重组。

结论：IL-34是一种新型内源性因子，可重塑高代谢M34巨噬细胞并促进其与T效应细胞的交叉调节从而引起RA的炎症性骨破坏。

出处：

Van Raemdonck, K., Umar, S., Palasiewicz, K., Volin, M.V., Elshabrawy, H.A., Romay, B., Tetali, C., Ahmed, A., Amin, M.A., Zomorrodi, R.K., Sweiss, N. and Shahrara, S. (2021), Interleukin-34 Reprograms Glycolytic and Osteoclastic Rheumatoid Arthritis Macrophages via Syndecan 1 and Macrophage Colony-Stimulating Factor Receptor. Arthritis Rheumatol, 73: 2003-2014. https://doi.org/10.1002/art.41792

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2021-12-04 lmm397

#关节炎#

27 0
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2021-12-04 minzju5052

#糖酵解#

51 0
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2021-12-04 ms4964546379600229

#类风湿#

30 0
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2021-12-04 ms1467340776200723

#风湿性关节炎#

33 0
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2021-12-03 10188348

有用，多谢分享

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