Experimental Neurology 258 (2014) 17–23

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Review

Pleiotropic molecules in axon regeneration and neuroinflammation Bradley T. Lang b, Jian Wang a, Angela R. Filous b, Ngan Pan Bennett Au c,d, Chi Him Eddie Ma c,d, Yingjie Shen a,⁎ a

Department of Neuroscience, Center for Brain and Spinal Cord Repair, The Ohio State University, Columbus, OH 43210, USA Case Western Reserve University, Cleveland, OH 44121, USA c Department of Biomedical Sciences, City University of Hong Kong, Tat Chee Avenue, Hong Kong d Centre for Biosystems, Neuroscience, and Nanotechnology, City University of Hong Kong, Tat Chee Avenue, Hong Kong b

a r t i c l e

i n f o

Article history: Received 24 September 2013 Revised 21 April 2014 Accepted 29 April 2014 Keywords: Neuroinflammation Axon regeneration Myelin-associated inhibitors and receptors Proteoglycans

a b s t r a c t Neuroinflammation is the foremost defense reaction of the nervous system to most if not all insults. Injuries to the central and peripheral nervous system (CNS and PNS) are followed by immediate activation of innate immune cells and infiltration of peripheral immune cells, amid waves of upregulation of numerous inflammatory mediators. Prolonged inflammation can lead to secondary tissue damage and prohibit regeneration of the injured nervous system. The regulation of inflammation and neuroregeneration are orchestrated through a complex network of signal transduction. Interestingly, many molecules play pleiotropic roles in both processes. Growing evidence implicates a handful of axon regeneration regulators in the processes of neuroinflammation, among which are the myelin and glial scar associated axon growth inhibitors and their axonal receptors. In this article, we will review the roles of these canonical axon regeneration regulators in neuroinflammation. Published by Elsevier Inc.

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . Nogo receptors (NgRs) . . . . . . . . . . . . . . . . . . . . Myelin-associated glycoprotein (MAG) . . . . . . . . . . . . . Paired immunoglobulin-like receptor B (PirB) . . . . . . . . . . Chondroitin sulfate- and heparan sulfate-proteoglycans (CSPGs and Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgment . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . HSPGs) . . . . . . . . . . . .

Introduction Traumatic injuries of the nervous system lead to acute inflammation, as well as axonal damage and cell death that result in broken neural circuits. At lesion sites, a variety of molecules are released into the extracellular space that are known as axon regeneration inhibitors. Among these, the most intensively studied are the chondroitin sulfate proteoglycans (CSPGs) secreted mainly by the reactive glial cells, and the myelin associated inhibitors (MAIs), including myelin-associated glycoprotein (MAG), Nogo-A, and oligodendrocyte-myelin glycoprotein

⁎ Corresponding author. E-mail address: [email protected] (Y. Shen).

http://dx.doi.org/10.1016/j.expneurol.2014.04.031 0014-4886/Published by Elsevier Inc.

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(OMgp). Receptors for these extracellular inhibitors are found on the surface of neurons and their ligand interactions lead to the formation of dystrophic growth cones and abortion of axon extension. To name a few, these include the Nogo receptor (NgR), p75 neurotrophin receptor (p75NTR), paired immunoglobulin-like receptor B (PirB), protein tyrosine phosphatase sigma (PTPRS), and leukocyte antigen related (LAR/PTPRF) (Akbik et al., 2012; Atwal et al., 2008; Dickendesher et al., 2012; Domeniconi et al., 2002; Fournier et al., 2001; Liu et al., 2002; Sharma et al., 2012; Shen et al., 2009; Wang et al., 2002a, 2002b; Yiu and He, 2006). Interestingly, the axon growth inhibitors also interact with the residential and infiltrating immune cells, as some of their receptors are as well expressed in these immune cells. Although these molecules have been intensively studied in axon regeneration, their roles in immune responses are less appreciated. In this

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B.T. Lang et al. / Experimental Neurology 258 (2014) 17–23

Myelin Debris

(A)

Nogo-66

Microglia/Macrophages

MAG

OMgp Lingo1

NgR

Neuron

NgR P75 or TROY

?

p75

PirB

PirB TrkB

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MAG-NgR and Nogo-NgR interaction leads to reduced myelin adhesion.

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Nogo-PirB interaction is speculated to curtail inflammatory responses and infiltration.

Axon growth inhibition by all three MAIs.

PTPRS or LAR

CD44

Neuron NgR 1&3 P75

HSPGs promote and CSPGs inhibit axon growth.

Unidentified Receptor

Microglia/Macrophages

HSPGs / CSPGs

(B)

Immediately following SCI, infiltration and proinflammatory responses of microglia/macrophages are inhibited by CSPGs, but likely promoted by HSPGs.

Fig. 1. Pleiotropic molecules in axon regeneration and neuroinflammation. MAIs (A) and proteoglycans (B) signal through receptors in neurons and microglia/macrophages. The same molecules can have both beneficial and detrimental impacts on the injured nervous system.

article, we will review emerging data on the involvement of these canonical axon regeneration regulators in neuroinflammation. Promoting axon regeneration and curtailing neuroinflammation are both crucial for post-injury recovery. A better understanding of their intertwined molecular mechanisms is important for the design of effective therapies (Fig. 1). Nogo receptors (NgRs) The Nogo receptor (NgR) family consists of three glycosylphosphatidylinositol (GPI)-anchored receptors: NgR1, the bona fide “Nogo receptor”, and its two homologues, NgR2 and NgR3 (Borrie et al., 2012). The NgRs are predominantly expressed by neurons throughout development and remain highly expressed in the adult

nervous system (Lauren et al., 2003). NgR1 is identified as a receptor of the MAIs, including Nogo-A, MAG, and OMgp (Domeniconi et al., 2002; Fournier et al., 2001; Liu et al., 2002; Wang et al., 2002b). In injured adult CNS, some studies showed that NgR1 mediates MAIinhibition of axon regeneration (Cafferty and Strittmatter, 2006; Kim et al., 2004; McGee et al., 2005), although there are controversies between research groups (Zheng et al., 2005). While denoted as Nogo receptors, neither NgR2 nor NgR3 binds to Nogo. NgR2 was instead found to be a receptor of MAG, and NgR3 does not interact with any of the MAIs (Lauren et al., 2007; Venkatesh et al., 2005). Recently, NgR1 and NgR3 were also identified as receptors for CSPGs (Dickendesher et al., 2012). Anchored to the cell membrane via GPI, the NgRs rely on coreceptors to mediate intracellular signaling. In neurons, NgR1 engages

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transmembrane receptors LINGO-1 and p75NTR (or TROY) to propagate MAI-inhibitory signals, whereas binding to CSPGs induce the formation of a receptor complex that includes NgR1, NgR3, and p75NTR (Dickendesher et al., 2012; Mi et al., 2004; Park et al., 2005; Wang et al., 2002a). Signaling through NgR receptor complexes inhibits neurite extension, axonal motility, and causes growth cone collapse (Borrie et al., 2012; Filbin, 2003). Although the NgRs have been extensively studied in axon regeneration, their roles in neuroinflammation are explored only recently (Borrie et al., 2012; David et al., 2008). In the immune system, the NgRs are expressed in macrophages, microglia, dendritic cells, and T cells (Fry et al., 2007; McDonald et al., 2011; Pool et al., 2009; Yan et al., 2012). Studies have shown that MAI-NgR signaling plays a crucial role in spatial regulation of the immune cells in neuropathologies. Following injuries in the nervous system, activated macrophages are recruited to the lesion sites where they participate in phagocytosis of cellular and myelin debris (Fawcett and Asher, 1999; Gaudet et al., 2011; Griffin et al., 2007; Hirata and Kawabuchi, 2002). In PNS, infiltrating macrophages eventually exit the injury site once this scavenger task is completed (Fry et al., 2007). Excessive and prolonged accumulation of macrophages at lesion sites leads to axonal dieback and further tissue damage (Gris et al., 2004; Horn et al., 2008; Kiefer et al., 2001; Popovich et al., 1999; Prineas and McLeod, 1976). Studies have found that the clearance of macrophages is regulated through the receptor–ligand interaction between NgRs and MAG. During post-injury regeneration in PNS, newly formed myelin facilitates macrophage clearance from the lesion sites by interacting with NgRs expressed on macrophages. After sciatic nerve injury, increasing numbers of infiltrating macrophages express both NgR1 and NgR2 on their cell surface. NgR1/2 depletion improves macrophage adhesion to myelin substrates. Either NgR1 or MAG deficiency impairs macrophage efflux from areas of remyelinated axons, suggesting a regulatory role of MAG-NgR interaction in macrophage clearance from the lesion sites (Fry et al., 2007). In a similar vein, NgR signaling also inhibits myelin adhesion by infiltrating dendritic cells and microglia, the resident immune cells of the CNS. Although initially expressed by immature dendritic cells, NgR1 and NgR2 expression is decreased upon dendritic cell maturation. As a result, mature dendritic cells adhere better to myelin substrates than immature dendritic cells. Depletion of NgR1 and NgR2 in these cells further enhances their adhesion to myelin (McDonald et al., 2011). Moreover, interaction between NgR and Nogo-66, a 66-amino-acid-residue domain of Nogo (including Nogo-A, B, and C), was found to inhibit the adhesion of cultured microglia on Nogo substrates (Yan et al., 2012). Collectively, these studies present evidence that MAI-NgR signaling in the immune cells inhibits their myelin adhesion, thereby regulating their spatial distribution. Unlike in the PNS where immune cells spontaneously evacuate during remyelination, CNS traumas, such as spinal cord injury (SCI), result in prolonged accumulation of microglia/macrophages in the injury area and persistent neuroinflammation. Although the precise mechanisms are not fully understood, it is speculated that MAI-NgR immune cell signaling may play a role. After SCI, macrophages that infiltrate into the lesion core to scavenge tissue debris eventually become entrapped in the epicenter cavity. Samuel David's lab has found that microglia/macrophages in injured spinal cord strongly express NgR, suggesting that these entrapped macrophages may be repelled and restrained by a barrier of the normal myelin surrounding the lesion cavity (David et al., 2008). This entrapment of macrophages could lead to prolonged inflammation within the lesion center, hampering the regeneration of severed axons in the area (Schwab et al., 2014–in this issue). However, there might also be a beneficial consequence of the restricted macrophage spreading, as this would protect the surrounding tissue from secondary damage caused by these neurotoxic cells. For decades, the NgRs and their MAI ligands have been intensively studied in the field of axon regeneration. Animal models with genetic depletion of these molecules were created to evaluate their effects on axonal plasticity and functional recovery after SCI (Bartsch et al., 1995;

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Cafferty and Strittmatter, 2006; Cafferty et al., 2010; David et al., 1995; Dickendesher et al., 2012; Dimou et al., 2006; Kim et al., 2003, 2004; Lee et al., 2010a, 2010b; Li et al., 1996; Shen et al., 1998; Simonen et al., 2003; Wang et al., 2011; Zheng et al., 2003; Zheng et al., 2005). In addition, therapeutic approaches, such as the IN-1 anti-Nogo-A monoclonal antibody and vaccinations against the MAIs, were designed to neutralize or reduce levels of MAIs so as to mitigate their inhibitory effects on axon growth after SCI (Ang et al., 2006; Caroni and Schwab, 1988; Chen et al., 2000; Huang et al., 1999; Sicotte et al., 2003). As most of the studies focused on the neuronal responses to these interventions, their effects on neuroinflammation have not been thoroughly evaluated. Although blocking the neuronal signaling of axon growth inhibitors is beneficial, interfering with MAI-NgR signaling in the immune cells may block myelin repulsion to these cells, resulting in their aberrant spreading and secondary tissue damage. Consequently, such detrimental neuroinflammatory effects could compromise the therapeutic outcome.

Myelin-associated glycoprotein (MAG) MAG is a member of the immunoglobulin superfamily and the first identified MAI expressed by myelinating glia including oligodendrocytes and Schwann cells (McKerracher et al., 1994; Mukhopadhyay et al., 1994; Salzer et al., 1987). The role of MAG in axonal regeneration is somewhat controversial and poorly understood. MAG promotes neurite outgrowth in embryonic and newborn neurons (Johnson et al., 1989; Turnley and Bartlett, 1998), but in postnatal and adult neurons, MAG inhibits neurite extension (McKerracher et al., 1994; Mukhopadhyay et al., 1994; Shen et al., 1998). It is not clear what causes neurons to switch their responses to MAG as they mature, although this paradox may be partially explained by higher levels of cAMP in developing neurons (Cai et al., 1999; Cao et al., 2010). While in vitro findings suggest that blocking MAG inhibitory signals in adult CNS should be beneficial for axonal regeneration, in vivo studies with MAG deficient mice do not consistently lead to improved regeneration (Bartsch et al., 1995; Cafferty et al., 2010; David et al., 1995; Lee et al., 2010b; Li et al., 1996). A possible explanation of this discrepancy is that depleting MAG may have additional effects besides its neuronal signaling, which could undermine the axon growth promoting benefits. In addition to its role in axon regeneration, MAG is also involved in neuroinflammation. It is implicated as an auto-antigen in autoimmune demyelinating neuropathologies such as anti-MAG neuropathy, multiple sclerosis (MS), polyneuropathy, and possibly after SCI (Andersson et al., 2002; Hayes et al., 2002; Steck et al., 1983, 2006). Patients suffering from demyelinating neuropathologies have elevated T- and B-cell immunoreactivity against MAG, as elevated anti-MAG antibody levels are detected in blood and cerebrospinal fluid (Andersson et al., 2002). In animal studies, injection of anti-MAG antibodies into sciatic and optic nerves leads to demyelination (Monaco et al., 1995; Sergott et al., 1988). In MS patients, loss of MAG due to autoimmune responses, accompanied by oligodendrocyte apoptosis, is detected in early disease onset prior to the formation of demyelinating plaques (Barnett and Sutton, 2006; Johnson et al., 1986). Significant downregulation of MAG is also found in lipopolysaccharide (LPS) and diphtheria toxin induced neuroinflammation, where it is also accompanied by a widespread loss of oligodendrocytes, progressive breakdown of myelin sheath, and accumulation of microglia followed by severe neuronal damage (Felts et al., 2005; Locatelli et al., 2012). In experimental autoimmune encephalomyelitis (EAE), an animal model of MS, genetic depletion of MAG leads to excessive microglia activation before EAE onset and exacerbates spinal cord axonal loss after induction of EAE (Jones et al., 2013). These findings indicate that preventing MAG loss may be neuroprotective, and therefore suppressing autoimmune attack of MAG or reducing levels of anti-MAG antibodies can be a potential therapeutic solution for these demyelinating neuropathologies. In fact, Rituximab, the current most effective drug for anti-MAG neuropathy,

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acts through the depletion of B cells that produce antibodies (Maurer et al., 2012; Steck et al., 2006). In SCI, B cell activation is a prominent post-injury process in rodents and humans and a trend of higher serum anti-MAG antibodies was observed in human patients, suggesting a possible injury-triggered autoimmune response (Ankeny and Popovich, 2010; Hayes et al., 2002). As the lesion site blood–brain-barrier is compromised after SCI, the increased levels of anti-MAG antibodies observed in serum may likely reflect the same changes inside the injured spinal cord. These increased anti-MAG antibodies could presumably have multiple effects both beneficial and detrimental. They may promote the clearance of myelin debris, and at the same time block MAG signaling through its receptors in neurons and immune cells. Whereas neutralizing MAG signaling in neurons would provide a relief of axon growth inhibition, blocking MAG-NgR interaction in microglia/macrophages can lead to aberrant spreading of these cells and thereby secondary tissue damage. Paired immunoglobulin-like receptor B (PirB) PirB was originally discovered as a receptor for major histocompatibility complex class I antigen (MHC-I) and is broadly expressed on cells of the hematopoietic system (Katz, 2006; Takai, 2005). In the CNS, PirB is detected in brain areas such as the cerebral cortex, hippocampus, cerebellum, and olfactory bulb, but not in spinal cord under normal conditions (Syken et al., 2006). In CNS pathologies such as transient cerebral ischemia and SCI, PirB expression is upregulated (Gou et al., 2013; Nakamura et al., 2011; Omoto et al., 2010). Recently, PirB and its human homologue leukocyte immunoglobulin-like receptor B2 (LILRB2) were identified as neuronal receptors for MAIs, including Nogo, MAG, and OMgp (Atwal et al., 2008). Binding of MAG to PirB leads to the association of PirB with p75NTR and TrkB, and subsequent downstream signaling (Fujita et al., 2011a, 2011b). In cultured neurons, interfering with PirB activity partially rescues neurite inhibition by the MAIs, and blocking both PirB and NgR activities leads to near-complete abortion of myelin inhibition (Atwal et al., 2008). However, PirB deficiency in vivo does not improve axonal regeneration after SCI or traumatic brain injury, which is reminiscent of other MAI ligands and receptors whose in vitro effects on axon growth fail to conform in vivo (Nakamura et al., 2011; Omoto et al., 2010). Like NgR, PirB is another MAI receptor that involves in inflammation. Several studies using PirB deficient mice showed that PirB suppresses macrophage activation (Karo-Atar et al., 2013; Kondo et al., 2013; Munitz et al., 2010; Pereira et al., 2004). PirB signaling in macrophages inhibits proinflammatory cytokine production induced by Toll-like receptor pathways, and suppresses matrix metalloproteinase secretion and integrin-regulated cell motility (Kondo et al., 2013; Munitz et al., 2010; Pereira et al., 2004). In the vascular system, surgical graft adaptation increases the expression of both PirB and Nogo-B, a Nogo-A homologue expressed by the vascular endothelium. Nogo–PirB interaction appears to play a vasculoprotective role by limiting macrophage infiltration and inflammatory responses (Kondo et al., 2013). After SCI, increased exposure of microglia/macrophages to Nogo-A at the injury site could conceivably signal through PirB in a similar fashion and suppress the inflammatory responses of these cells. It would be interesting to investigate in PirB deficient mice whether these immune cells become hyperactive after SCI, rendering increased inflammatory responses and secondary tissue damage beyond the lesion center. In such a scenario, the benefits of axon growth promotion by removing PirB neuronal signaling would be compromised by deleterious effects of neuroinflammation, thus explaining the lack of regeneration outcome in PirB deficient mice. Chondroitin sulfate- and heparan sulfate-proteoglycans (CSPGs and HSPGs) CSPGs and HSPGs are major components of the extracellular matrix (ECM) produced by various cell types, and are found in all vertebrate

tissues and organs. In the nervous system, their spatiotemporal expression is tightly regulated throughout development and upon injuries (Asher et al., 2000; Bloechlinger et al., 2004; Hsueh and Sheng, 1999; Jones et al., 2003; Massey et al., 2006; McKeon et al., 1991; Milev et al., 1998; Oohira et al., 1994; Pindzola et al., 1993; Properzi et al., 2008; Stipp et al., 1994). The dynamic regulation of proteoglycan expression is consistent with their functional roles, as HSPGs and CSPGs are both crucial players in shaping neural circuits and regulating neuroplasticity (Alilain et al., 2011; Bandtlow and Zimmermann, 2000; Bovolenta and Fernaud-Espinosa, 2000; Brittis et al., 1992; Maeda et al., 2011; Wilson and Snow, 2000). In neurons, both CSPGs and HSPGs interact with the same receptors, including PTPRS, LAR, NgR1, and NgR3 (Coles et al., 2011; Dickendesher et al., 2012; Fisher et al., 2011; Shen et al., 2009). Interestingly, HSPGs and CSPGs often have opposite effects on neuronal behavior. In the developing nervous system, many CSPGs function as repulsive ligands, whereas HSPGs present attractive guidance cues to migrating axons (Brittis et al., 1992; Kantor et al., 2004; Wang et al., 2012). In cultured neurons, CSPGs inhibit, while HSPGs promote, neurite outgrowth (Coles et al., 2011; Snow et al., 1990, 1991). Upon CNS injuries, upregulated CSPGs at the lesion site form a potent inhibitory barrier that prevents the regeneration of severed axons. Treatment with Chondroitinase ABC, an enzyme that degrades chondroitin sulfate chains, improves axonal plasticity and functional recovery after SCI (Bartus et al., 2012; Busch and Silver, 2007; Davies et al., 1997; Garcia-Alias and Fawcett, 2012; McKeon et al., 1991). In contrast, intracerebral infusion of Glypican, an HSPG that promotes axon growth, improves anatomical regeneration and functional recovery after ischemic brain injury (Hill et al., 2012). Although well known as potent axon regeneration inhibitors, CSPGs do play beneficial roles in immune modulation after SCI (see review article by Gaudet and Popovich, 2014–in this issue). Following SCI, increasing levels of CSPGs are deposited at the lesion area by reactive glial cells. In acute stage after injury, these CSPGs prevent the infiltration of blood-borne macrophages into the lesion epicenter, and induce microglia to acquire a noncytotoxic and neuroprotective phenotype through CD44 receptor signaling. Immediate inhibition of CSPG production after SCI dramatically increases infiltrating myeloid cells into the lesion site, significantly attenuates insulin-like growth factor 1 (IGF-1) production by microglia/macrophages, and increases tumor necrosis factor alpha (TNF-alpha) levels, resulting in impaired functional motor recovery and increased tissue loss. In contrast, CSPG synthesis inhibition two days after injury improves recovery (Rolls et al., 2008). CSPGs therefore play dichotomous roles in acute SCI by eliciting neuroprotective effects through the immune cells, while at the same time inhibiting axon growth in neurons. Studies by Rolls et al. also suggest that delayed CSPG invention is critical for achieving optimal recovery outcomes. Besides their roles in promoting neurite extension, HSPGs are also known to play many roles in immune responses (Selvan et al., 1996). For instance, HSPGs expressed by activated endothelial cells stimulate macrophage production of proinflammatory cytokines, such as IL-1α. HSPGs also localize and present chemokines to leukocytes, and regulate their adhesion and extravasation. In neuroinflammation induced by cerebral microinjection of LPS or amyloid-β, heparan sulfate mediates the activation of microglia and astrocytes and the infiltration of blood-borne macrophages. Overexpression of heparanase, an endoglucuronidase that specifically degrades heparan sulfate, significantly attenuates LPS-induced macrophage infiltration and microglia production of proinflammatory factors such as TNFα and IL-1β (Zhang et al., 2012). The expression level of heparanase is normally low in adult mouse brain, but transiently upregulated after insults such as stroke (Li et al., 2012). Similarly, in adult rat spinal cord, only a subpopulation of astrocytes normally expresses heparinase. Astrocyte expression of heparinase, however, is elevated in response to TGF-β1, a proinflammatory cytokine present at high level in injured spinal cord (Zhang et al., 2006). This transient induction of heparanase may possibly reflect a spontaneous attempt by the CNS to eliminate heparan sulfate in order to attenuate

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inflammation in the acute phase after insults, suggesting that despite their potent axon growth promoting effects in neurons, HSPGs can impose detrimental proinflammatory effects in early stage of injuries. Discussion The molecular mechanisms of neuroinflammation and axon regeneration are often intertwined. This review is certainly not exhaustive in presenting such evidence. Instead, we intend to raise a discussion on such a topic that concerns both research communities of neural injury and neuroinflammation. What we often learn from these examples of pleiotropic molecules is that their roles may be more complicated than simply beneficial or detrimental during neural repair. The dichotomy makes it challenging to design treatment strategies targeting these molecules. However, dissecting the spatiotemporal molecular regulation could reveal opportunities for therapeutic interventions. Cell type specific targeting strategy should be considered when interfering with these pleiotropic molecules. Knocking down MAI receptors selectively in neurons, for example, may promote axonal plasticity without triggering inflammatory side effects. Additionally, optimizing the timing for treatment is another way to take advantage of the temporal regulation of these molecular events. After SCI, therapies targeting the proteoglycan signaling are likely to be more effective only after acute stage, as CSPG depletion or HSPG supplement immediately after injury may elicit deleterious neuroinflammation. Acknowledgment We thank Professor Jerry Silver for the helpful comments. Yingjie Shen is supported by startup fund from the Department of Neuroscience, The Ohio State University. Chi Him Eddie Ma is supported in part by ECS (CityU 161212) and GRF (CityU 160813) grants from The Research Grants Council of the Hong Kong Special Administrative Region Government, Centre for Biosystems, Neuroscience, and Nanotechnology at City University of Hong Kong, and Seed Funding (7003028). References Akbik, F., Cafferty, W.B., Strittmatter, S.M., 2012. Myelin associated inhibitors: a link between injury-induced and experience-dependent plasticity. Exp. Neurol. 235, 43–52. Alilain, W.J., Horn, K.P., Hu, H., Dick, T.E., Silver, J., 2011. Functional regeneration of respiratory pathways after spinal cord injury. Nature 475, 196–200. Andersson, M., Yu, M., Soderstrom, M., Weerth, S., Baig, S., Solders, G., Link, H., 2002. Multiple MAG peptides are recognized by circulating T and B lymphocytes in polyneuropathy and multiple sclerosis. Eur. J. Neurol. 9, 243–251. Ang, B.T., Xu, G., Xiao, Z.C., 2006. Therapeutic vaccination for central nervous system repair. Clin. Exp. Pharmacol. Physiol. 33, 541–545. Ankeny, D.P., Popovich, P.G., 2010. B cells and autoantibodies: complex roles in CNS injury. Trends Immunol. 31, 332–338. Asher, R.A., Morgenstern, D.A., Fidler, P.S., Adcock, K.H., Oohira, A., Braistead, J.E., Levine, J.M., Margolis, R.U., Rogers, J.H., Fawcett, J.W., 2000. Neurocan is upregulated in injured brain and in cytokine-treated astrocytes. J. Neurosci. 20, 2427–2438. Atwal, J.K., Pinkston-Gosse, J., Syken, J., Stawicki, S., Wu, Y., Shatz, C., Tessier-Lavigne, M., 2008. PirB is a functional receptor for myelin inhibitors of axonal regeneration. Science 322, 967–970. Bandtlow, C.E., Zimmermann, D.R., 2000. Proteoglycans in the developing brain: new conceptual insights for old proteins. Physiol. Rev. 80, 1267–1290. Barnett, M.H., Sutton, I., 2006. The pathology of multiple sclerosis: a paradigm shift. Curr. Opin. Neurol. 19, 242–247. Bartsch, U., Bandtlow, C.E., Schnell, L., Bartsch, S., Spillmann, A.A., Rubin, B.P., Hillenbrand, R., Montag, D., Schwab, M.E., Schachner, M., 1995. Lack of evidence that myelin-associated glycoprotein is a major inhibitor of axonal regeneration in the CNS. Neuron 15, 1375–1381. Bartus, K., James, N.D., Bosch, K.D., Bradbury, E.J., 2012. Chondroitin sulphate proteoglycans: key modulators of spinal cord and brain plasticity. Exp. Neurol. 235, 5–17. Bloechlinger, S., Karchewski, L.A., Woolf, C.J., 2004. Dynamic changes in glypican-1 expression in dorsal root ganglion neurons after peripheral and central axonal injury. Eur. J. Neurosci. 19, 1119–1132. Borrie, S.C., Baeumer, B.E., Bandtlow, C.E., 2012. The Nogo-66 receptor family in the intact and diseased CNS. Cell Tissue Res. 349, 105–117.

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