Using a mouse model of spinal injury, Michal Schwartz and colleagues tested the effect of macrophages on the recovery process and demonstrate an important anti-inflammatory role for a subset of infiltrating monocyte-derived macrophages that is dependent upon their expression of interleukin 10.

Monocyte-derived macrophages (mo-M⌽s

The inflammatory response in the injured spinal cord, an immune privileged site, has been mainly associated with the poor prognosis. However, recent data demonstrated that, in fact, some leukocytes, namely monocytes, are pivotal for repair due to their alternative anti-inflammatory phenotype. Given the pro-inflammatory milieu within the traumatized spinal cord, known to skew monocytes towards a classical phenotype, a pertinent question is how parenchymal-invading monocytes acquire resolving properties essential for healing, under such unfavorable conditions. In light of the spatial association between resolving (interleukin (IL)-10 producing) monocytes and the glial scar matrix chondroitin sulfate proteoglycan (CSPG), in this study we examined the mutual relationship between these two components. By inhibiting the de novo production of CSPG following spinal cord injury, we demonstrated that this extracellular matrix, mainly known for its ability to inhibit axonal growth, serves as a critical template skewing the entering monocytes towards the resolving phenotype. In vitro cell culture studies demonstrated that this matrix alone is sufficient to induce such monocyte polarization. Reciprocal conditional ablation of the monocyte-derived macrophages concentrated at the lesion margins, using diphtheria toxin, revealed that these cells have scar matrix-resolving properties. Replenishment of monocytic cell populations to the ablated mice demonstrated that this extracellular remodeling ability of the infiltrating monocytes requires their expression of the matrix-degrading enzyme, matrix metalloproteinase 13 (MMP-13), a property that was found here to be crucial for functional recovery. Altogether, this study demonstrates that the glial scar-matrix, a known obstacle to regeneration, is a critical component skewing the encountering monocytes towards a resolving phenotype. In an apparent feedback loop, monocytes were found to regulate scar resolution. This cross-regulation between the glial scar and monocytes primes the resolution of this interim phase of spinal cord repair, thereby providing a fundamental platform for the dynamic healing response.

Inadequate axonal regeneration is a common phenomenon occurring following acute injury to the central nervous system (CNS), and is often associated with permanent neurological deficits. The injured axons attempting to regenerate face the inhospitable environment of the CNS scar, which can hinder axonal growth and sprouting. In addition, in response to the insult, intense activation and infiltration of immune cells take place. Both the scar tissue and immune response, which have received a bad reputation in the context of CNS repair are essential for the overall recovery from CNS injuries, but are not optimally controlled. The glial scar contributes to protection of the spared neural tissues by establishing a boundary between damaged and salvageable tissue, and by educating the immune cells to promote the healing of the CNS tissue. In turn, the immune cells, and in particular the infiltrating macrophages, exert several functions at the lesion site, including resolution of the microglial response, control of scar tissue degradation, and production of growth factors; thereby, promoting neuronal survival, axonal regeneration, and tissue remodeling. As axonal regeneration and tissue remodeling are viewed as critical steps for the overall functional recovery following CNS injury, a detailed understanding of the mechanisms underlying the timely formation and degradation of the CNS scar, and its crosstalk with the inflammatory response, are of great importance, both biologically and clinically.

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