A novel LncRNA SPIRE1/miR-181a-5p/PRLR axis in mandibular bone marrow-derived mesenchymal stem cells regulates the Th17/Treg immune balance through the JAK/STAT3 pathway in periodontitis

作者全名："Shao, Bingyi; Zhou, Duo; Wang, Jie; Yang, Deqin; Gao, Jing"

作者地址："[Shao, Bingyi; Zhou, Duo; Wang, Jie; Yang, Deqin; Gao, Jing] Stomatol Hosp Chongqing Med Univ, Northern Dept Endodont, Chongqing 401147, Peoples R China; [Shao, Bingyi; Zhou, Duo; Wang, Jie; Yang, Deqin; Gao, Jing] Chongqing Key Lab Oral Dis & Biomed Sci, Chongqing 401147, Peoples R China; [Shao, Bingyi; Zhou, Duo; Wang, Jie; Yang, Deqin; Gao, Jing] Chongqing Municipal Key Lab Oral Biomed Engn Highe, Chongqing 401147, Peoples R China"

通信作者："Gao, J (通讯作者)，Stomatol Hosp Chongqing Med Univ, Northern Dept Endodont, Chongqing 401147, Peoples R China.; Gao, J (通讯作者)，Chongqing Key Lab Oral Dis & Biomed Sci, Chongqing 401147, Peoples R China.; Gao, J (通讯作者)，Chongqing Municipal Key Lab Oral Biomed Engn Highe, Chongqing 401147, Peoples R China."

来源：AGING-US

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:001044526700033

JCR分区：Q2

影响因子：3.9

年份：2023

卷号：15

期号：14

开始页：7124

结束页：7145

文献类型：Article

关键词：periodontitis; LncRNA SPIRE1; miR-181a-5p; PRLR; mesenchymal stem cells; immunomodulation; STAT3 pathway

摘要："Periodontitis is a microbial-related chronic inflammatory disease associated with imbalanced differentiation of Th17 cells and Treg cells. Bone marrow-derived mesenchymal stem cells (BM-MSCs) possess wide immunoregulatory properties. Long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) contribute to the immunomodulation in the pathological mechanisms of inflammatory diseases. However, critical lncRNAs/miRNAs involved in immunomodulation of mandibular BM-MSCs largely remain to be identified. Here, we explored the molecular mechanisms behind the defective immunomodulatory ability of mandibular BM-MSCs under the periodontitis settings. We found that mandibular BM-MSCs from P. gingivalis-induced periodontitis mice had significantly reduced expression of LncRNA SPIRE1 than that from normal control mice. LncRNA SPIRE1 knockdown in normal BM-MSCs caused Th17/Treg cell differentiation imbalance during the coculturing of BM-MSCs and CD4 T cells. In addition, LncRNA SPIRE1 was identified as a competitive endogenous RNA that sponges miR-181a-5p in BM-MSCs. Moreover, miR-181a-5p inhibition attenuated the impact of LncRNA SPIRE1 knockdown on the ability of BM-MSCs in modulating Th17/Treg balance. Prolactin receptor (PRLR) was validated as a downstream target of miR-181a-5p. Notably, targeted knockdown of LncRNA SPIRE1 or PRLR or transfection of miR-181a-5p mimics activated the JAK/STAT3 signaling in normal BM-MSCs, while treatment with STAT3 inhibitor C188-9 restored the immunomodulatory properties of periodontitis-associated BM-MSCs. Furthermore, BM-MSCs with miR-181a-5p inhibition or PRLR-overexpression showed enhanced in vivo immunosuppressive properties in the periodontitis mouse model. Our results indicate that the JAK/STAT3 pathway is involved in the immunoregulation of BM-MSCs, and provide critical insights into the development of novel targeted therapies against periodontitis."

基金机构：National Natural Science Foundation of China [32000577]

基金资助正文：This work was supported by the National Natural Science Foundation of China (No. 32000577) .