Samia Khan

Background: Spinal cord injuries (SCI) encase a wide variety of origins that are characterized by damage to the spinal cord leading to a loss of function.¹ The global rate of SCI is between 250,000 and 500,000 people annually and can result in patients having permanent disability, economic burden, and psychological impact.^2,3 Secondary injury related to SCI, including inflammation, glial scar maturation, and neuronal death, can further hinder functional recovery.³ The only FDA-approved medication for SCI is methylprednisolone, which can only be administered within eight hours after injury and thus may not be applicable to all SCI patients with older injuries.¹ Microglia, specifically anti-inflammatory microglia, have a role in neuroprotection and healing after SCI, in particular via the phagocytosis of debris. Microglia also play a role in glial scar formation through astrocytes following injury.¹ Because enhancing neuroprotection and limiting secondary injury rea of interest to increased functional recovery, this suggests that targeting the activation and upregulation microglia is of potential therapeutic of SCI.¹

Objective(s): In this review, microglial contribution to SCI recovery, wound healing, and a delivery vehicle for therapeutics related to microglia were investigated.

Search Methods: Using the PubMed database, an online search was conducted on studies between 2018 and 2024. The following MeSH terms and keywords were used: “Spinal Cord Injuries,” “immunology,” “microglia,” and “scar formation.”

Results: The complex relationship between microglia and inflammation following SCI is key to developing of effective therapies. SCI results in neuroinflammation involving monocyte-derived macrophages (MDMs) and microglia.⁴ Pharmacological depletion of microglia in mice using PLX5622 exacerbates locomotor deficits, highlighting their role in functional recovery.⁴ Without microglia, recruited MDMs contribute to secondary injury by limiting the astrocytic border formation around the lesion site.⁴ Targeting the HMGB1-RAGE axis attenuates pro-inflammatory microglial induction, which enhances recovery in rat SCI models.⁵ Inflammation is also mediated by Plexin-B2 gene expression.⁶ In activated microglia and macrophages, this directs injury corralling and wound compaction, while its depletion results in larger, unresolved injuries.⁶ Scar formation following SCI, which can limit axon growth past the lesion site, involves microglia proliferation and expression of genes promoting extracellular matrix formation, wound healing, immune response regulation, and peptidase inhibitors.⁷ Neonatal microglia and adult microglia treated with proteinase inhibitors expressed in neonates reduce scar formation and enhance axon regeneration, emphasizing microglia’s role in inflammation resolution and scar-free healing.⁷ Additionally, a hyaluronan and methylcellulose hydrogel delivering fat extract (HAMC/FE) promotes recovery in mice by minimizing secondary tissue damage and inducing anti-inflammatory microglial polarization via the STAT6/Arg-1 pathway.⁸ Targeting microglial induction is a promising strategy for SCI therapy, with potential implications for inflammation resolution and scar-free healing.

Conclusion: Microglia are crucial in SCI recovery, with both pro- and anti-inflammatory subtypes involved. They contribute to recovery by modulating inflammation through the HMGB1-RAGE axis and influencing wound healing and scar formation. Using HAMC/FE as a delivery vehicle of SCI therapeutics shows promise for enhancing anti-inflammatory polarization. All these data support the need to further investigate how targeting and modulating microglial changes and the balance between pro- and anti-inflammatory microglial response can enhance functional recovery.

Works Cited:

1. Hu X, Xu W, Ren Y, et al. Spinal cord injury: molecular mechanisms and therapeutic interventions. Sig Transduct Target Ther. 2023;8(1):245. doi:10.1038/s41392-023-01477-6
2. Quadri SA, Farooqui M, Ikram A, et al. Recent update on basic mechanisms of spinal cord injury. Neurosurg Rev. 2020;43(2):425-441. doi:10.1007/s10143-018-1008-3
3. Anjum A, Yazid MD, Fauzi Daud M, et al. Spinal cord injury: pathophysiology, multimolecular interactions, and underlying recovery mechanisms. IJMS. 2020;21(20):7533. doi:10.3390/ijms21207533
4. Brennan FH, Li Y, Wang C, et al. Microglia coordinate cellular interactions during spinal cord repair in mice. Nat Commun. 2022;13(1):4096. doi:10.1038/s41467-022-31797-0
5. Fan H, Tang HB, Chen Z, et al. Inhibiting HMGB1-RAGE axis prevents pro-inflammatory macrophages/microglia polarization and affords neuroprotection after spinal cord injury. J Neuroinflammation. 2020;17(1):295. doi:10.1186/s12974-020-01973-4
6. Zhou X, Wahane S, Friedl MS, et al. Microglia and macrophages promote corralling, wound compaction and recovery after spinal cord injury via Plexin-B2. Nat Neurosci. 2020;23(3):337-350. doi:10.1038/s41593-020-0597-7
7. Li Y, He X, Kawaguchi R, et al. Microglia-organized scar-free spinal cord repair in neonatal mice. Nature. 2020;587(7835):613-618. doi:10.1038/s41586-020-2795-6
8. Xu G, Xu S, Zhang Y, et al. Cell‐free extracts from human fat tissue with a hyaluronan‐based hydrogel attenuate inflammation in a spinal cord injury model through m2 microglia/microphage polarization. Small. 2022;18(17):2107838. doi:10.1002/smll.202107838