hUMSC-Exosomes suppress TREM1-p38 MAPK signaling via HMGB1-dependent mechanisms to reprogram microglial function and promote neuroprotection in ischemic stroke
Abstract Background Ischemic stroke induces profound neuroinflammation, where microglial activation exacerbates secondary brain injury. Human umbilical mesenchymal stem cell-derived exosomes (hUMSC-Exos) exhibit therapeutic potential, but their mechanisms in modulating microglial responses remain in...
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| Language: | English |
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BMC
2025-08-01
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| Series: | Journal of Nanobiotechnology |
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| Online Access: | https://doi.org/10.1186/s12951-025-03652-z |
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| author | Zengyu Zhang Rong Ji Zhuohang Liu Zhiwen Jiang Min Chu Yong Wang Jing Zhao |
| author_facet | Zengyu Zhang Rong Ji Zhuohang Liu Zhiwen Jiang Min Chu Yong Wang Jing Zhao |
| author_sort | Zengyu Zhang |
| collection | DOAJ |
| description | Abstract Background Ischemic stroke induces profound neuroinflammation, where microglial activation exacerbates secondary brain injury. Human umbilical mesenchymal stem cell-derived exosomes (hUMSC-Exos) exhibit therapeutic potential, but their mechanisms in modulating microglial responses remain incompletely understood. Results Following intranasal administration, hUMSC-Exos selectively accumulated in ischemic brain regions and were internalized by microglia. In transient middle cerebral artery occlusion (tMCAO) mice, hUMSC-Exos improved neurological outcomes, reduced neuronal apoptosis, and promoted a sustained shift in microglial polarization toward an anti-inflammatory phenotype—evidenced by suppressed pro-inflammatory and elevated anti-inflammatory markers in peri-infarct areas. These effects were replicated in LPS/IFN-γ-stimulated primary microglia and BV2 cells. Microglia-specific RNA sequencing revealed that hUMSC-Exos reversed tMCAO-induced pro-inflammatory and migratory transcriptional programs, concurrently suppressing p38 MAPK while activating immunoregulatory pathways. TREM1 emerged as a critical node, with hUMSC-Exos downregulating its expression in microglia; pharmacological TREM1 inhibition (LP17) synergistically augmented the suppression of microglial activation, migration, and proliferation. Mechanistically, hUMSC-Exos attenuated NF-κB/p38 MAPK signaling, with TREM1 functioning upstream of p38 (validated by overexpression/reversal). Proteomic analysis identified HMGB1 as a key exosomal cargo—its blockade (glycyrrhizin) partially reversed hUMSC-Exos-mediated effects, restoring TREM1 expression and pro-inflammatory cytokine release, thus positioning HMGB1 upstream of TREM1. Conclusions Our findings delineate a novel HMGB1-TREM1-p38 MAPK axis through which hUMSC-Exos mitigate post-stroke neuroinflammation. By delivering HMGB1, hUMSC-Exos inhibit TREM1-dependent NF-κB/p38 activation, reprogram microglial function, and confer neuroprotection. Validated across in vivo, primary, and BV2 microglial models, and supported by multi-omics analyses, this study establishes hUMSC-Exos as a promising cell-free therapy targeting microglial reprogramming for ischemic stroke recovery. Graphical abstract |
| format | Article |
| id | doaj-art-63e5823ffc8a465fa0aeba4d94b370e5 |
| institution | Kabale University |
| issn | 1477-3155 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Nanobiotechnology |
| spelling | doaj-art-63e5823ffc8a465fa0aeba4d94b370e52025-08-24T11:48:48ZengBMCJournal of Nanobiotechnology1477-31552025-08-0123112610.1186/s12951-025-03652-zhUMSC-Exosomes suppress TREM1-p38 MAPK signaling via HMGB1-dependent mechanisms to reprogram microglial function and promote neuroprotection in ischemic strokeZengyu Zhang0Rong Ji1Zhuohang Liu2Zhiwen Jiang3Min Chu4Yong Wang5Jing Zhao6Department of Neurology, Minhang Hospital, Fudan UniversityDepartment of Neurology, Minhang Hospital, Fudan UniversityDepartment of Neurology, Minhang Hospital, Fudan UniversityDepartment of Neurosurgery, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan UniversityDepartment of Geriatrics, Shanghai Geriatric Medical CenterDepartment of Neurology, Zhongshan Hospital, Fudan UniversityDepartment of Neurology, Minhang Hospital, Fudan UniversityAbstract Background Ischemic stroke induces profound neuroinflammation, where microglial activation exacerbates secondary brain injury. Human umbilical mesenchymal stem cell-derived exosomes (hUMSC-Exos) exhibit therapeutic potential, but their mechanisms in modulating microglial responses remain incompletely understood. Results Following intranasal administration, hUMSC-Exos selectively accumulated in ischemic brain regions and were internalized by microglia. In transient middle cerebral artery occlusion (tMCAO) mice, hUMSC-Exos improved neurological outcomes, reduced neuronal apoptosis, and promoted a sustained shift in microglial polarization toward an anti-inflammatory phenotype—evidenced by suppressed pro-inflammatory and elevated anti-inflammatory markers in peri-infarct areas. These effects were replicated in LPS/IFN-γ-stimulated primary microglia and BV2 cells. Microglia-specific RNA sequencing revealed that hUMSC-Exos reversed tMCAO-induced pro-inflammatory and migratory transcriptional programs, concurrently suppressing p38 MAPK while activating immunoregulatory pathways. TREM1 emerged as a critical node, with hUMSC-Exos downregulating its expression in microglia; pharmacological TREM1 inhibition (LP17) synergistically augmented the suppression of microglial activation, migration, and proliferation. Mechanistically, hUMSC-Exos attenuated NF-κB/p38 MAPK signaling, with TREM1 functioning upstream of p38 (validated by overexpression/reversal). Proteomic analysis identified HMGB1 as a key exosomal cargo—its blockade (glycyrrhizin) partially reversed hUMSC-Exos-mediated effects, restoring TREM1 expression and pro-inflammatory cytokine release, thus positioning HMGB1 upstream of TREM1. Conclusions Our findings delineate a novel HMGB1-TREM1-p38 MAPK axis through which hUMSC-Exos mitigate post-stroke neuroinflammation. By delivering HMGB1, hUMSC-Exos inhibit TREM1-dependent NF-κB/p38 activation, reprogram microglial function, and confer neuroprotection. Validated across in vivo, primary, and BV2 microglial models, and supported by multi-omics analyses, this study establishes hUMSC-Exos as a promising cell-free therapy targeting microglial reprogramming for ischemic stroke recovery. Graphical abstracthttps://doi.org/10.1186/s12951-025-03652-zhUMSC-exosomesIschemic strokeTREM1P38 MAPK signalingMicrogliaNeuroinflammation |
| spellingShingle | Zengyu Zhang Rong Ji Zhuohang Liu Zhiwen Jiang Min Chu Yong Wang Jing Zhao hUMSC-Exosomes suppress TREM1-p38 MAPK signaling via HMGB1-dependent mechanisms to reprogram microglial function and promote neuroprotection in ischemic stroke Journal of Nanobiotechnology hUMSC-exosomes Ischemic stroke TREM1 P38 MAPK signaling Microglia Neuroinflammation |
| title | hUMSC-Exosomes suppress TREM1-p38 MAPK signaling via HMGB1-dependent mechanisms to reprogram microglial function and promote neuroprotection in ischemic stroke |
| title_full | hUMSC-Exosomes suppress TREM1-p38 MAPK signaling via HMGB1-dependent mechanisms to reprogram microglial function and promote neuroprotection in ischemic stroke |
| title_fullStr | hUMSC-Exosomes suppress TREM1-p38 MAPK signaling via HMGB1-dependent mechanisms to reprogram microglial function and promote neuroprotection in ischemic stroke |
| title_full_unstemmed | hUMSC-Exosomes suppress TREM1-p38 MAPK signaling via HMGB1-dependent mechanisms to reprogram microglial function and promote neuroprotection in ischemic stroke |
| title_short | hUMSC-Exosomes suppress TREM1-p38 MAPK signaling via HMGB1-dependent mechanisms to reprogram microglial function and promote neuroprotection in ischemic stroke |
| title_sort | humsc exosomes suppress trem1 p38 mapk signaling via hmgb1 dependent mechanisms to reprogram microglial function and promote neuroprotection in ischemic stroke |
| topic | hUMSC-exosomes Ischemic stroke TREM1 P38 MAPK signaling Microglia Neuroinflammation |
| url | https://doi.org/10.1186/s12951-025-03652-z |
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