The Glial Scar-Monocyte Interplay: A Pivotal Resolution Phase in Spinal Cord Repair

Abstract

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.

The glial scar in spinal cord injury and repair

“…However, increasing evidence over the past decade has changed this perception due to the existence of alternative antiinflammatory monocytes [5] . The alternative activation of mononuclear (IL-10 producing) phagocytes, in contrast to the classic phenotype of pro-inflammatory features, has a strong matrix-resolving property to degenerate the glial scar depending on the expression of the matrix-degrading enzyme MMP-13 [101,102] . More interestingly, CSPGs, the predominant component of glial-scar ECM, directly activate microglia/macrophages via the CD44 receptor and modulate neurotrophic factor secretion by these cells during the first two days after injury [18] .…”

The role of the immune system in central nervous system plasticity after acute injury

“…Apoptotic neutrophils within the lesion border can affect nearby reactive microglia/macrophages by promoting a switch towards the alternative anti-inflammatory phenotype (M2) (Filardy et al, 2010). Once polarized, M2-like macrophages start producing anti-inflammatory IL-10 and increase the expression of MMP-13, which allows the remodelling of the scar matrix into a more permissive environment for axonal re-growth (Shechter et al, 2011). This polarization towards the IL-10 hi IL-12 low M2-like anti-inflammatory phenotype is also dependent on IL-6 secretion by astrocytes and on the direct interaction of CSPGs with microglia/macrophages.…”

“…MMP-9, Collagenase, Gelatinase, Elastase (Fang et al, 1999;Bao Dang et al, 2013), MPO (Baldus et al, 2001;Shechter et al, 2011) Elastase (Kitson et al, 1998;Jacobsen et al, 2007) Tryptase Chymase (Weerth et al, 2003;Tchougounova et al, 2005), MMP-2, MMP-9 (Fang et al, 1999;Stirling et al, 2009) (Rahpeymai et al, 2006;Hao et al, 2010), BDNF, NT-3 (Hammarberg, et al 2000;Shinjyo et al, 2009) Sema4A, NT-3 (Bénard et al, 2008;Ishii et al, 2012) NAA (modulation of H 2 O 2 -induced apoptosis) (Warrington et al, 2004;Mantovani et al, 2011) Angiogenesis C5 (Norrby, 2002;Langer et al, 2010) VEGF (Scapini et al, 2004;Ribatti et al, 2011), MMP-9 (Justicia et al, 2003;Riboldi et al, 2005) PDGF, TNF-α and VEGF (Horiuchi and Weller, 1997) VEGF, TNF-α and β, FGF, MMP (Norrby et al, 2002) tryptase and chymase (Ribatti et al, 2011) VEGF (Riboldi et al, 2005), TNF-α, transdifferentiation in ELCs (Fernandez Pujol et al, 2001), trogocytosis of VEGF receptor …”

Myeloid-Specific Blockade of Notch Signaling by RBP-J Knockout Attenuates Spinal Cord Injury Accompanied by Compromised Inflammation Response in Mice

“…Blocking microglial activation [7,8] or depleting blood-derived macrophages [9,10] has been reported to gain beneficial outcomes after SCI. However, macrophages can also promote axon regeneration [11][12][13], provide neurotrophic factors [14], and regulate glial scar remodeling [15] under certain conditions. The diversity of macrophage functions in SCI may be a Bei-Yu Chen, Min-Hua Zheng, and Yan Chen contributed equally to this work.…”