Macrophage activation and its role in repair and pathology after spinal cord injury

Abstract

The injured spinal cord does not heal properly. In contrast, tissue repair and functional recovery occur after skin or muscle injuries. The reason for this dichotomy in wound repair is unclear but inflammation, and specifically macrophage activation, likely plays a key role. Macrophages have the ability to promote the repair of injured tissue by regulating transitions through different phase of the healing response. In the current review we compare and contrast the healing and inflammatory responses between spinal cord injuries and tissues that undergo complete wound resolution. Through this comparison, we identify key macrophage phenotypes that are inaptly triggered or absent after spinal cord injury and discuss spinal cord stimuli that contribute to this maladaptive response. Sequential activation of classic, pro-inflammatory, M1 macrophages and alternatively activated, M2a, M2b, and M2c macrophages occurs during normal healing and facilitates transitions through the inflammatory, proliferative, and remodeling phases of repair. In contrast, in the injured spinal cord, pro-inflammatory macrophages potentiate a prolonged inflammatory phase and remodeling is not properly initiated. The desynchronized macrophage activation after spinal cord injury is reminiscent of the inflammation present in chronic, non-healing wounds. By refining the role macrophages play in spinal cord injury repair we bring to light important areas for future neuroinflammation and neurotrauma research. This article is part of a Special Issue entitled SI: Spinal cord injury.

Tocotrienol alleviates inflammation and oxidative stress in a rat model of spinal cord injury via suppression of transforming growth factor-β

“…Experiments have confirmed that TGF-β is expressed in the early stage of cartilage formation, in cartilage callus mesenchymal cells, immature chondrocytes and mature chondrocytes (32). Furthermore, previous studies show that the extracellular expression of TGF-β1 initially appeared in the hematoma in injured area after the spinal cord injury, and the expression is subsequently enhanced in the cytoplasm and nucleus of astrocytes, intramedullary and extramedullary capillary endothelial cells and motor neurons (33,34). The present results indicate that treatment with tocotrienols significantly inhibited TGF-β protein expression in SCI rats.…”

Mechanisms Involved in the Remyelinating Effect of Sildenafil

“…Taking these results together suggests that sildenafil is promoting a mixed microglia phenotype, since an early increase in the expression of Arg-1, COX-2 was observed accompanied by an increase expression of IL-10 and IL-6; these features are recently being associated with M2b/c microglia/macrophage phenotype which shows immune-regulatory and immune-suppressor properties by promoting inflammatory resolution, tissue repair, production of anti-inflammatory and prostaglandins (Colton 2009, Chhor et al 2013, Gensel and Zhang 2015, Ransohoff and Perry 2009, Wu et al 2013) and even more, this phenotype has been associated with OPCs differentiation (Miron et al 2013). Recent studies have indentified another mixed microglia/macrophage phenotype not classically M1 nor alternatively activated M2 cells; they were called "resolution-phase" macrophages (rM), since this particular phenotype has been observed in macrophages isolated from the resolving phase of acute inflammation.…”

“…Moreover, COX-2 increase has been associated with M2b/c (immuneregulatory/immune-suppressor) phenotype associated with the production of anti-inflammatory prostaglandins (Chhor et al 2013, Ransohoff and Perry 2009, Wu et al 2013, and wound healing after spinal cord injury (Gensel and Zhang 2015). On the other hand, within sildenafil treatment doses tendency to decrease M1 phenotype was observed, suggesting that PDE5 inhibitor may be promoting healing and regeneration of tissue by enhancing a M2-like phenotype and diminishing the pro-inflammatory phenotype.…”

“…Microglia/macrophage phenotypes can be recognized by changes in the expression of specific molecules. NOS-2, TNFα, COX-2, and IL-1β are characteristic molecules of a M1 phenotype while arginase-1, CD206, Ym-1 and FIZZ-1 are considered M2-phenotype markers 21 (Chhor et al 2013, Fernando et al 2014, Gensel and Zhang 2015. However, recent studies in vitro and in vivo have revealed that reactive microglia/macrophages are able to co-express M1 and M2 markers.…”

“…Furthermore, macrophages treated with IL-4 in vitro, were shown to produce IL-6 while co-expressing the M2 characteristic molecule CD206, and the co-expression of IL-6 did not affect immunosuppressive properties of the M2 phenotype macrophages (Casella et al 2016). Other studies aimed at characterizing specific molecules to delineate and identify microglia /macrophage phenotypes have also shown co-expression of the antiand pro-inflammatory phenotype markers (Chhor et al 2013, Gensel andZhang 2015).…”