PMID- 32345320 OWN - NLM STAT- MEDLINE DCOM- 20210319 LR - 20210319 IS - 1742-2094 (Electronic) IS - 1742-2094 (Linking) VI - 17 IP - 1 DP - 2020 Apr 28 TI - LncGBP9/miR-34a axis drives macrophages toward a phenotype conducive for spinal cord injury repair via STAT1/STAT6 and SOCS3. PG - 134 LID - 10.1186/s12974-020-01805-5 [doi] LID - 134 AB - BACKGROUND: Acute spinal cord injury (SCI) could cause mainly two types of pathological sequelae, the primary mechanical injury, and the secondary injury. The macrophage in SCI are skewed toward the M1 phenotype that might cause the failure to post-SCI repair. METHODS: SCI model was established in Balb/c mice, and the changes in macrophage phenotypes after SCI were monitored. Bioinformatic analyses were performed to select factors that might regulate macrophage polarization after SCI. Mouse bone marrow-derived macrophages (BMDMs) were isolated, identified, and induced for M1 or M2 polarization; the effects of lncRNA guanylate binding protein-9 (lncGBP9) and suppressor of cytokine signaling 3 (SOCS3) on macrophages polarization were examined in vitro and in vivo. The predicted miR-34a binding to lncGBP9 and SOCS3 was validated; the dynamic effects of lncGBP9 and miR-34a on SOCS3, signal transducer and activator of transcription 1 (STAT1)/STAT6 signaling, and macrophage polarization were examined. Finally, we investigated whether STAT6 could bind the miR-34a promoter to activate its transcription. RESULTS: In SCI Balb/c mice, macrophage skewing toward M1 phenotypes was observed after SCI. In M1 macrophages, lncGBP9 silencing significantly decreased p-STAT1 and SOCS3 expression and protein levels, as well as the production of Interleukin (IL)-6 and IL-12; in M2 macrophages, lncGBP9 overexpression increased SOCS3 mRNA expression and protein levels while suppressed p-STAT6 levels and the production of IL-10 and transforming growth factor-beta 1 (TGF-beta1), indicating that lncGBP9 overexpression promotes the M1 polarization of macrophages. In lncGBP9-silenced SCI mice, the M2 polarization was promoted on day 28 after the operation, further indicating that lncGBP9 silencing revised the predominance of M1 phenotype at the late stage of secondary injury after SCI, therefore improving the repair after SCI. IncGBP9 competed with SOCS3 for miR-34a binding to counteract miR-34a-mediated suppression on SOCS3 and then modulated STAT1/STAT6 signaling and the polarization of macrophages. STAT6 bound the promoter of miR-34a to activate its transcription. CONCLUSIONS: In macrophages, lncGBP9 sponges miR-34a to rescue SOCS3 expression, therefore modulating macrophage polarization through STAT1/STAT6 signaling. STAT6 bound the promoter of miR-34a to activate its transcription, thus forming two different regulatory loops to modulate the phenotype of macrophages after SCI. FAU - Zhou, Jiahui AU - Zhou J AD - Department of Orthopedics, The Third Xiangya Hospital, Central South University, Changsha, 410013, China. FAU - Li, Zhiyue AU - Li Z AD - Department of Orthopedics, The Third Xiangya Hospital, Central South University, Changsha, 410013, China. FAU - Wu, Tianding AU - Wu T AD - Department of Spine Surgery, Xiangya Hospital of Central South University, Changsha, 410008, PR of China. FAU - Zhao, Qun AU - Zhao Q AD - Department of Orthopedics, The Third Xiangya Hospital, Central South University, Changsha, 410013, China. FAU - Zhao, Qiancheng AU - Zhao Q AD - Department of Orthopedics, The Third Xiangya Hospital, Central South University, Changsha, 410013, China. FAU - Cao, Yong AU - Cao Y AD - Department of Spine Surgery, Xiangya Hospital of Central South University, Changsha, 410008, PR of China. caoyong1912@163.com. LA - eng GR - 81902224/National Natural Science Foundation of China/ GR - 2019JJ50959/Natural Science Foundation of Hunan Province/ PT - Journal Article DEP - 20200428 PL - England TA - J Neuroinflammation JT - Journal of neuroinflammation JID - 101222974 RN - 0 (MIRN34a microRNA, mouse) RN - 0 (MicroRNAs) RN - 0 (RNA, Long Noncoding) RN - 0 (STAT1 Transcription Factor) RN - 0 (STAT6 Transcription Factor) RN - 0 (Socs3 protein, mouse) RN - 0 (Stat1 protein, mouse) RN - 0 (Stat6 protein, mouse) RN - 0 (Suppressor of Cytokine Signaling 3 Protein) SB - IM MH - Animals MH - Gene Expression Regulation/*physiology MH - Macrophage Activation/*physiology MH - Macrophages/cytology/metabolism MH - Mice MH - Mice, Inbred BALB C MH - MicroRNAs/*metabolism MH - Phenotype MH - RNA, Long Noncoding/*metabolism MH - STAT1 Transcription Factor/metabolism MH - STAT6 Transcription Factor/metabolism MH - Signal Transduction/*physiology MH - Spinal Cord Injuries/metabolism/*pathology MH - Suppressor of Cytokine Signaling 3 Protein/metabolism PMC - PMC7187522 OTO - NOTNLM OT - Macrophage polarization OT - MiR-34a OT - SOCS3 OT - STAT1/STAT6 OT - lncGBP9 OT - spinal cord injury (SCI) COIS- The authors declare that they have no competing interests. EDAT- 2020/04/30 06:00 MHDA- 2021/03/20 06:00 PMCR- 2020/04/28 CRDT- 2020/04/30 06:00 PHST- 2019/12/22 00:00 [received] PHST- 2020/04/06 00:00 [accepted] PHST- 2020/04/30 06:00 [entrez] PHST- 2020/04/30 06:00 [pubmed] PHST- 2021/03/20 06:00 [medline] PHST- 2020/04/28 00:00 [pmc-release] AID - 10.1186/s12974-020-01805-5 [pii] AID - 1805 [pii] AID - 10.1186/s12974-020-01805-5 [doi] PST - epublish SO - J Neuroinflammation. 2020 Apr 28;17(1):134. doi: 10.1186/s12974-020-01805-5.