PMID- 37716974 OWN - NLM STAT- MEDLINE DCOM- 20230918 LR - 20231123 IS - 1477-3155 (Electronic) IS - 1477-3155 (Linking) VI - 21 IP - 1 DP - 2023 Sep 16 TI - Exosomes derived from LPS-preconditioned bone marrow-derived MSC modulate macrophage plasticity to promote allograft survival via the NF-kappaB/NLRP3 signaling pathway. PG - 332 LID - 10.1186/s12951-023-02087-8 [doi] LID - 332 AB - OBJECTIVES: This study investigated whether exosomes from LPS pretreated bone marrow mesenchymal stem cells (LPS pre-MSCs) could prolong skin graft survival. METHODS: The exosomes were isolated from the supernatant of MSCs pretreated with LPS. LPS pre-Exo and rapamycin were injected via the tail vein into C57BL/6 mice allografted with BALB/c skin; graft survival was observed and evaluated. The accumulation and polarization of macrophages were examined by immunohistochemistry. The differentiation of macrophages in the spleen was analyzed by flow cytometry. For in vitro, an inflammatory model was established. Specifically, bone marrow-derived macrophages (BMDMs) were isolated and cultured with LPS (100 ng/ml) for 3 h, and were further treated with LPS pre-Exo for 24 h or 48 h. The molecular signaling pathway responsible for modulating inflammation was examined by Western blotting. The expressions of downstream inflammatory cytokines were determined by Elisa, and the polarization of macrophages was analyzed by flow cytometry. RESULTS: LPS pre-Exo could better ablate inflammation compared to untreated MSC-derived exosomes (BM-Exo). These loaded factors inhibited the expressions of inflammatory factors via a negative feedback mechanism. In vivo, LPS pre-Exo significantly attenuated inflammatory infiltration, thus improving the survival of allogeneic skin graft. Flow cytometric analysis of BMDMs showed that LPS pre-Exo were involved in the regulation of macrophage polarization and immune homeostasis during inflammation. Further investigation revealed that the NF-kappaB/NLRP3/procaspase-1/IL-1beta signaling pathway played a key role in LPS pre-Exo-mediated regulation of macrophage polarization. Inhibiting NF-kappaB in BMDMs could abolish the LPS-induced activation of inflammatory pathways and the polarization of M1 macrophages while increasing the proportion of M2 cells. CONCLUSION: LPS pre-Exo are able to switch the polarization of macrophages and enhance the resolution of inflammation. This type of exosomes provides an improved immunotherapeutic potential in prolonging graft survival. CI - (c) 2023. BioMed Central Ltd., part of Springer Nature. FAU - Zhang, PeiYao AU - Zhang P AD - Department of Orthopedics, Hand & Microsurgery Surgery, Xiangya Hospital of Central South University, Xiangy Road, Changsha, 410008, Hunan, China. FAU - Wu, Panfeng AU - Wu P AD - Department of Orthopedics, Hand & Microsurgery Surgery, Xiangya Hospital of Central South University, Xiangy Road, Changsha, 410008, Hunan, China. FAU - Khan, Umar Zeb AU - Khan UZ AD - Department of Orthopedics, Hand & Microsurgery Surgery, Xiangya Hospital of Central South University, Xiangy Road, Changsha, 410008, Hunan, China. FAU - Zhou, Zekun AU - Zhou Z AD - Department of Orthopedics, Hand & Microsurgery Surgery, Xiangya Hospital of Central South University, Xiangy Road, Changsha, 410008, Hunan, China. FAU - Sui, Xinlei AU - Sui X AD - Department of Orthopedics, Hand & Microsurgery Surgery, Xiangya Hospital of Central South University, Xiangy Road, Changsha, 410008, Hunan, China. FAU - Li, Cheng AU - Li C AD - Department of Orthopedics, Hand & Microsurgery Surgery, Xiangya Hospital of Central South University, Xiangy Road, Changsha, 410008, Hunan, China. FAU - Dong, Kangkang AU - Dong K AD - Department of Orthopedics, Hand & Microsurgery Surgery, Xiangya Hospital of Central South University, Xiangy Road, Changsha, 410008, Hunan, China. FAU - Liu, Yongjun AU - Liu Y AD - Department of Orthopedics, Hand & Microsurgery Surgery, Xiangya Hospital of Central South University, Xiangy Road, Changsha, 410008, Hunan, China. FAU - Qing, Liming AU - Qing L AD - Department of Orthopedics, Hand & Microsurgery Surgery, Xiangya Hospital of Central South University, Xiangy Road, Changsha, 410008, Hunan, China. qingliming@csu.edu.cn. FAU - Tang, Juyu AU - Tang J AD - Department of Orthopedics, Hand & Microsurgery Surgery, Xiangya Hospital of Central South University, Xiangy Road, Changsha, 410008, Hunan, China. tangjuyu@csu.edu.cn. LA - eng GR - 2019JJ50940/Natural Science Foundation of Hunan Province/ GR - 81901978/National Natural Science Foundation of China Youth Fund/ GR - 81871577/National Natural Science Foundation of China/ PT - Journal Article DEP - 20230916 PL - England TA - J Nanobiotechnology JT - Journal of nanobiotechnology JID - 101152208 RN - 0 (NF-kappa B) RN - 0 (Lipopolysaccharides) RN - 0 (NLR Family, Pyrin Domain-Containing 3 Protein) SB - IM MH - Mice MH - Animals MH - Mice, Inbred C57BL MH - *NF-kappa B MH - Lipopolysaccharides/pharmacology MH - NLR Family, Pyrin Domain-Containing 3 Protein MH - *Exosomes MH - Bone Marrow MH - Signal Transduction MH - Allografts PMC - PMC10504750 OTO - NOTNLM OT - Allograft OT - Exosome OT - LPS preconditioning OT - Macrophage polarization OT - Mesenchymal stromal cells COIS- The authors declare that they have no competing interests. EDAT- 2023/09/17 00:41 MHDA- 2023/09/18 12:42 PMCR- 2023/09/16 CRDT- 2023/09/16 23:16 PHST- 2023/04/12 00:00 [received] PHST- 2023/08/29 00:00 [accepted] PHST- 2023/09/18 12:42 [medline] PHST- 2023/09/17 00:41 [pubmed] PHST- 2023/09/16 23:16 [entrez] PHST- 2023/09/16 00:00 [pmc-release] AID - 10.1186/s12951-023-02087-8 [pii] AID - 2087 [pii] AID - 10.1186/s12951-023-02087-8 [doi] PST - epublish SO - J Nanobiotechnology. 2023 Sep 16;21(1):332. doi: 10.1186/s12951-023-02087-8.