Frontiers in Immunology (Feb 2024)

The secretome of macrophages has a differential impact on spinal cord injury recovery according to the polarization protocol

  • José Lentilhas-Graça,
  • José Lentilhas-Graça,
  • José Lentilhas-Graça,
  • Diogo J. Santos,
  • Diogo J. Santos,
  • João Afonso,
  • João Afonso,
  • Andreia Monteiro,
  • Andreia Monteiro,
  • Andreia G. Pinho,
  • Andreia G. Pinho,
  • Vera M. Mendes,
  • Marta S. Dias,
  • Marta S. Dias,
  • Eduardo D. Gomes,
  • Eduardo D. Gomes,
  • Rui Lima,
  • Rui Lima,
  • Luís S. Fernandes,
  • Luís S. Fernandes,
  • Fernando Fernandes-Amorim,
  • Fernando Fernandes-Amorim,
  • Inês M. Pereira,
  • Inês M. Pereira,
  • Nídia de Sousa,
  • Nídia de Sousa,
  • Jorge R. Cibrão,
  • Jorge R. Cibrão,
  • Aline M. Fernandes,
  • Aline M. Fernandes,
  • Sofia C. Serra,
  • Sofia C. Serra,
  • Luís A. Rocha,
  • Luís A. Rocha,
  • Jonas Campos,
  • Jonas Campos,
  • Tiffany S. Pinho,
  • Tiffany S. Pinho,
  • Susana Monteiro,
  • Susana Monteiro,
  • Bruno Manadas,
  • António J. Salgado,
  • António J. Salgado,
  • Ramiro D. Almeida,
  • Ramiro D. Almeida,
  • Nuno A. Silva,
  • Nuno A. Silva

DOI
https://doi.org/10.3389/fimmu.2024.1354479
Journal volume & issue
Vol. 15

Abstract

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IntroductionThe inflammatory response after spinal cord injury (SCI) is an important contributor to secondary damage. Infiltrating macrophages can acquire a spectrum of activation states, however, the microenvironment at the SCI site favors macrophage polarization into a pro-inflammatory phenotype, which is one of the reasons why macrophage transplantation has failed.MethodsIn this study, we investigated the therapeutic potential of the macrophage secretome for SCI recovery. We investigated the effect of the secretome in vitro using peripheral and CNS-derived neurons and human neural stem cells. Moreover, we perform a pre-clinical trial using a SCI compression mice model and analyzed the recovery of motor, sensory and autonomic functions. Instead of transplanting the cells, we injected the paracrine factors and extracellular vesicles that they secrete, avoiding the loss of the phenotype of the transplanted cells due to local environmental cues.ResultsWe demonstrated that different macrophage phenotypes have a distinct effect on neuronal growth and survival, namely, the alternative activation with IL-10 and TGF-β1 (M(IL-10+TGF-β1)) promotes significant axonal regeneration. We also observed that systemic injection of soluble factors and extracellular vesicles derived from M(IL-10+TGF-β1) macrophages promotes significant functional recovery after compressive SCI and leads to higher survival of spinal cord neurons. Additionally, the M(IL-10+TGF-β1) secretome supported the recovery of bladder function and decreased microglial activation, astrogliosis and fibrotic scar in the spinal cord. Proteomic analysis of the M(IL-10+TGF-β1)-derived secretome identified clusters of proteins involved in axon extension, dendritic spine maintenance, cell polarity establishment, and regulation of astrocytic activation.DiscussionOverall, our results demonstrated that macrophages-derived soluble factors and extracellular vesicles might be a promising therapy for SCI with possible clinical applications.

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