**2.4. Inhibitory molecules**

via the NF-kB translocation pathway. Phagocytic activity can induce NF-kB activation [15, 16], and other mediators such as matrix metalloproteases (MMPs), and cytokines TNFα, IL-1, IL-8,

**Microglia** are a unique myeloid cell population, derived from the yolk sac during a narrow time window during development (before vascularization or definitive hematopoiesis) in the embryo. Microglia cells, present in the CNS parenchyma, are sustained by the proliferation of

Their response following pathological stimuli is characterized by an accumulation at the lesion site and the release of various bioactive molecules. Two categories of molecules are released, some are cytotoxic or pro-inflammatory, and others may aid survival and regeneration. Resident monocytes are the first cell types to respond after injury within 1–2 h, which starts the initial acute inflammatory response accompanied by an expression of TNFα and IL-1 (M1 phenotype). This leads to the recruitment of other immune cells. M1 macrophages promote phagocytosis. Eight hours after injury, the production of pro-inflammatory cytokines is terminated, thus promoting the differentiation of macrophages into an anti-inflammatory M2 phenotype with the expression of arginase 1 and a mannose receptor (CD206). M2 macrophages promote angiogenesis and matrix remodeling, while suppressing destructive immunity [18]. The ratio

These findings correlate with accumulating evidence pointing to a chronological time line expression of different degeneration- and regeneration-associated genes that are involved in the pathogenesis and endogenous repair or plasticity during days to months following SCI.

Microglia activation may be beneficial, deleterious or neutral [8, 9]. Neurons express cell surface glycoproteins (CD22, CD47, CD200, and NCAM) to prevent microglia activation [10, 19]. A relationship between the nervous and immune system has been studied this past decade. Indeed, glial cells (microglia and astrocytes) not only perform supportive and nutritive roles for neurons, but also serve to defend the CNS. On the other hand, excessive and prolonged glial cell activation may result in more severe and chronic neuronal damage, leading to neu-

Neurons are able to control microglia with two types of signals: "On" or "Off" [20]. Off signals (TGF-β, CD22, CX3CL1, neurotransmitters, and CD20) are found in healthy conditions to maintain homeostasis and also restrict microglial activities under inflammatory conditions to prevent damage to healthy tissue. Conversely, "On" signals [CCL21, CXCL10, and MMP3 (from apoptotic neurons)] are produced by damaged and impaired neurons to activate microg-

Glial scar is the accompanying pathological phenomenon of various CNS injuries. The site of injury is infiltrated by macrophages from the bloodstream, fibroblasts, astrocytes, microglia, and oligodendrocytes [8]. Later, precursors of oligodendrocytes and meningeal cells are activated.

and TGF-β [17].

4 Essentials of Spinal Cord Injury Medicine

resident progenitors, independently of blood cells.

M1/M2 varies in terms of the microenvironment.

roinflammation and neurodegeneration [11, 13].

lia (pro- or anti-inflammatory) [21].

**2.3. Glial scar**

**2.2. Neuro-glial interactions**

NOGO inhibitory protein [25, 26], myelin glycoprotein oligodendrocyte (OMGP) [27], myelinassociated glycoprotein (MAG) [28] together with secondary inhibitors, including the large group of chondroitin sulfate proteoglycans (CSPGs), are among the major inhibitory molecules that block axonal regeneration [24, 29]. While blocking the penetration of axons, they contribute to the formation of so-called blind clusters, unable to form functional connections with terminal neurons. These pathological formations often cause painful irritable syndrome [30].

Inhibitory CSPGs are synthesized by neurons and glial cells. They play an important role in the physiological development of the CNS, such as cell migration, maturation, differentiation, survival, and tissue homeostasis, but in the case of disruption of tissue homeostasis, increase their expression and consequently inhibit regeneration [31]. These molecules interact extensively with extracellular matrix components [32], for example, with laminin, fibronectin, tenascin, and collagen [33]. Additionally, they bind to growth factors, midkine, pleiotrophin, fibroblast growth factor [34], or inhibitory growth factors such as semaphorins [19] and contribute to the formation of a glial scar that inhibits regeneration of axons [35]. NG2 glycoprotein, which belongs to the most important inhibitors of the CSPGs group, is produced by oligodendrocytes precursor, meningeal cells and macrophages [36]. Accumulation of NG2 was seen at the site of injury, where it blocks regeneration of the axons [31]. Co-expression of NG2 and PDGF-α receptors in the same population of CNS cells confirmed its specific expression in oligodendrocyte precursors [37]. NG2-positive oligodendrocyte precursor cells are often the first cells to respond to injury. Unlike microglia, reactive oligodendrocyte changes are local and occur only in the immediate vicinity of the injury. Previous experiments confirm the initiation of spontaneous regeneration in SCI, as reflected by the incidence of GAP-43-positive axons. They were found in the segments above the lesion at first week [38]. In the central lesion, which forms a mechanical and chemical barrier, the inhibitory proteoglycan NG2 was significantly enhanced [39]. Immunohistochemical analyses using specific NG2/GAP-43 antibody confirmed that increased accumulation of NG2-positive cells at the central injury creates a barrier for successful diffusion and further ingrowth of GAP-43-labeled axonal fibers at acute phase [38]. Sequential administration of ChABC enzyme caused degradation of NG2 glycoprotein, which modified the extracellular matrix and created a tolerant environment for longer term recovery (2–3 weeks).
