Until now, the main factor determining the phenotype of the monocytes was thought to be the surrounding cytokine milieu[16],[17],[20]. 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. == Introduction == Every year, spinal cord injury (SCI), a debilitating condition with a limited prognosis for recovery, paralyzes around 130,000 people. The poor recovery of the central nervous system (CNS), a delicate tissue that cannot tolerate toxic conditions, is generally attributed to the hostile local milieu created at the trauma site. Two major barriers to repair that have been identified include the local inflammatory response, acknowledged for its neurotoxic potential, and the creation of the glial scar, known to impair regeneration[1],[2],[3]. The axonal growth inhibitory effects of the scar matrix were supported by numerousin vitrostudies demonstrating that such molecules cause neurite retraction and growth cone collapse[4], along with their well-defined developmental role in formation of boundaries. Accordingly, research efforts and clinical manipulations were directed at attempts to eliminate and reorganize the chemical components of the glial scar[5],[6]and to suppress the ensuing immune response[7]. Recent studies, however, indicated that the scar Vinflunine Tartrate and some immune cell populations each have independent, though transient, positive roles. The glial scar was shown to provide an SOS response, a distress signal initiated by the tissue in response to the trauma that demarcates the lesion site and restores the isolation of the CNS from the circulation[8],[9]. Likewise, leukocytes were demonstrated to promote removal of tissue debris, secrete neurotrophic factors, and support axonal regeneration[10],[11],[12],[13],[14],[15]. Recently, a pivotal role for recovery was attributed to monocytes that infiltrate the damaged CNS due to their non-classical anti-inflammatory/resolving properties[11],[14]. These cells were shown to produce the anti-inflammatory cytokine, interleukin 10 (IL-10) and to terminate the local microglial response. Based on their inflammation-resolving properties, these monocyte-derived cells correspond to the previously TRAILR3 identified macrophage subset with immunoregulatory properties, the resolving/regulatory macrophages (rM), observed in wound healing[16],[17], or myeloid derived suppressor cells (MDSC), which occur in cancer. Comparable suppressive monocytes were identified also in other pathologies, including myocardial infarction[18],[19]. Advances in the field of myeloid cells, revealing macrophage heterogeneity and monocyte plasticity, brought this often neglected population back into the spotlight. Until now, the main factor determining the phenotype of the monocytes was thought to be the surrounding cytokine milieu[16],[17],[20]. While a pro-inflammatory milieu, enriched in either IFN- or TNF-, skews Vinflunine Tartrate monocytes towards a classical pro-inflammatory (M1) phenotype, a Th2/anti-inflammatory environment, composed of IL-4 and IL-13, or IL-10 and TGF, generates alternatively-activated (M2) or rM, endowed with Vinflunine Tartrate healing properties[11],[14]. Given the pro-inflammatory environment at the site of trauma[21], in the current study, we aimed to identify the factors that maintain the healing properties of the infiltrating monocytes under such pro-inflammatory conditions. In light of the immunomodulatory effects recently attributed to the glial scar matrix component, chondroitin sulfate proteoglycan (CSPG), in microglial education[9], together with the spatial association between the infiltrating monocytes and this glial scar component[9], we investigated here the mutual regulation between these two key processes in the course of the response to injury. We show that CSPG is an essential platform, skewing the infiltrating monocytes towards their resolving anti-inflammatory phenotype. In an apparent reciprocal loop, the monocyte-derived cells acquire matrix-degrading properties enabling their resolution of the glial.
Until now, the main factor determining the phenotype of the monocytes was thought to be the surrounding cytokine milieu[16],[17],[20]
