Predicting neurological recovery after traumatic spinal cord injury by time-resolved analysis of monocyte subsets

Spinal Cord Injury
Original Article
Open Access

R. Heller


May 22, 2021


SCI is a devastating injury with profound physical and psychosocial consequences1. It progresses through primary and secondary phases, with the latter characterized by intricate inflammatory responses. Monocyte-derived macrophages (MDMs) have been identified as key contributors to these inflammatory processes and tissue remodeling after SCI. The classification of macrophages into pro-inflammatory M1 and anti-inflammatory M2 subtypes has provided insights into their roles in SCI pathogenesis and recovery. Achieving a balance between pro-inflammatory and anti-inflammatory macrophages is crucial for promoting neuroprotection and tissue regeneration.

Traumatic spinal cord injury (SCI) elicits a complex cascade of inflammatory responses involving immune cells, cytokines, and chemokines, which significantly influence the injury outcome and subsequent recovery. The interplay between immune cells, particularly monocyte subsets and lymphocytes, along with cytokine expression, trace element concentrations, and clinical factors, plays a crucial role in the survival of neurons and the regenerative processes following SCI2. Understanding these immunological processes is essential for developing effective therapeutic strategies to improve outcomes in SCI patients.

In addition to macrophages, T cells also play a significant role in SCI. T cells infiltrate the injured spinal cord and release cytokines that contribute to both secondary tissue damage and tissue repair. The balance between pro-inflammatory T helper 1 (Th1) cells and anti-inflammatory T helper 2 (Th2) cells is critical for the immune response and functional recovery after SCI. Manipulating this balance and modulating the immune response through immunomodulatory approaches have shown promise in preclinical models of SCI.

The immune response in SCI is regulated by various signaling molecules and immune modulators. Chemokines such as monocyte chemoattractant protein-1 (MCP-1) and stromal cell-derived factor-1 (SDF-1) play essential roles in immune cell recruitment and activation at the injury site. Understanding the mechanisms underlying immune cell recruitment and activation can lead to the development of targeted therapeutic interventions.

Advancements in immunotherapy have opened new avenues for SCI treatment. Cell-based therapies, particularly mesenchymal stem cell (MSC) transplantation, have demonstrated immunomodulatory properties. MSCs can suppress inflammation, promote tissue regeneration, and enhance functional recovery in SCI models. These findings suggest the potential of immunomodulatory approaches, including cell-based therapies, to improve outcomes in SCI patients.

In summary, immunological processes significantly impact the pathophysiology and recovery of SCI. The interplay between immune cells, cytokines, and chemokines determines the injury outcome. Manipulating the immune response and developing targeted immunomodulatory therapies hold promise for improving outcomes in SCI patients. Understanding the dynamics of monocyte subsets, lymphocyte responsiveness, cytokine expression, trace element concentrations, and clinical factors contributes to identifying prognostic factors and potential therapeutic targets in traumatic SCI. Further research in this area is needed to advance our understanding and translate these findings into effective clinical interventions.


Patients and Methods

In the present study3 we examined prospectively 18 (three female, 15 male) patients after traumatic spinal cord injury. Blood samples were drawn at admission and 4h, 9h, 12h, 1 and 3days as well as 1 and 2weeks and 1, 2 and 3months after the trauma. Analysis of cytokines (CCL2, IL-10, enolase 2, CXCL12, TGF-β1, TGF-β2) was performed using a multiplex cytokine panel. Plasma trace element concentrations of selenium, copper and zinc were determined by total reflection X-ray fluorescence analysis; neopterin, selenoprotein P (SELENOP) and ceruloplasmin (CP) by enzyme-linked immunosorbent assay; and selenium binding protein 1 (SELENBP1) by luminometric immunoassay. The responsive potential of lymphocytes was assessed using transformation tests. The monocyte subsets (classical, intermediate, and non-classical) and expression of CD14, CD16, CXCR4 and intracellular IL-10 were identified using a multi-colour flow cytometry analysis.


The dynamics of the cluster of intermediate CD14−/CD16+/IL10+/CXCR4int monocytes differed significantly between patients with an absence of neurological remission (G0) from those with an improvement (G1) by 1 or 2 American Spinal Injury Association Impairment Scale (AIS) steps (Kruskal-Wallis Test, P=0.010, G0<G1, AIS+: 1<G1, AIS+: 2) in the first 24h. These dynamics were associated inversely with an increase in enolase and SELENBP1 14 days after the injury.


In the elastic net regularized model, we identified an association between the increase of a subpopulation of intermediate CD14−/CD16+/IL10+/CXCR4int monocytes and exacerbated immune response within 24h after the injury. These findings were reflected in the consistently elevated response to mitogen stimulation of the lymphocytes of patients with significant neurological remission. Early elevated concentrations of CD14−/CD16+/IL10+/CXCR4int monocytes were related to higher odds of CNS regeneration and enhanced neurological remission. The cluster dynamics of CD14−/CD16+/IL10+/CXCR4int monocytes in the early-acute phase after the injury revealed a maximum of prognostic information regarding neurological remission (mean parameter estimate: 0.207; selection count: 818/1000 repetitions).

We conclude that early dynamics in monocyte subsets allow a good prediction of recovery from traumatic spinal cord injury.



BibTeX citation:
  author = {Heller, R. and Seelig, J. and Crowell, H. and Pilz, M. and
    Haubruck, P. and Sun, Q. and Schomburg, L. and Daniel, V. and
    Moghaddam, A. and Biglari, B.},
  title = {Predicting Neurological Recovery After Traumatic Spinal Cord
    Injury by Time-Resolved Analysis of Monocyte Subsets},
  journal = {Brain},
  date = {2021-05-22},
  url = {},
  doi = {10.1093/brain/awab203},
  langid = {en}
For attribution, please cite this work as:
Heller, R. et al. Predicting neurological recovery after traumatic spinal cord injury by time-resolved analysis of monocyte subsets. Brain (2021) doi:10.1093/brain/awab203.

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