Traumatic damage to the nervous system including spinal cord injury (SCI) causes extensive inflammation and the invasion of microglia in and around the affected regions. Previous work has shown, that activation and accumulation of microglia around the epicenter of the lesion is thought to be involved in the quite limited axonal recovery of the CNS (Kitayama et al., 2011; Popovich et al., 1999). The molecular mechanisms blocking neurite regrowth and regeneration are not completely understood but they implicate microglia-derived substances acting as axon growth inhibitors.
Results of the present thesis support evidence that activation of microglia attenuate neurite outgrowth of co-cultured neurons without direct cell-cell surface contact.
Thus, we hypothesized that microglia-derived secreted molecules must be responsible for the poor axonal elongation (Fig. 8 A). By performing experimental manipulations I found that the induction of microglial iNOS and the presence of NO were responsible for blocking neurite growth following growth cone collapse (Scheiblich and Bicker, 2015b). Intriguingly, inhibition of iNOS/NO production via
Discussion 29
induction of HO-1/CO signaling not only attenuated the inflammatory response of reactive microglia (see discussion before) but also allowed for neurite outgrowth (Scheiblich and Bicker, 2015a). In support of these observations we found, that the regulation of neurite outgrowth is caused downstream the NO pathway (Fig. 8 B) (Roloff et al., 2015).
Figure 8: Neurite outgrowth of human model neurons (magenta) is regulated by microglia (green). (A) Microglial activation result in the induction of the inducible nitric oxide synthase (iNOS) and subsequently in the release of nitric oxide (NO). The presence of NO blocks neurite outgrowth of the neurons. However, induction of heme oxygenase-1 (HO-1) and the release of carbon monoxide (CO) rescue the detrimental effects of microglia-derived NO on neurite outgrowth. (B) Sine both, NO and CO, have the potential to bind to the soluble guanylyl cyclase (sGC) and thus to regulate the conversion of guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP) by the protein kinase G (PKG) it is likely that considerable parts of neurite growth are regulated downstream the sGC/cGMP cascade. In support of this, treatment with the commercial pain reliever Ibuprofen (RhoA (Ras homolog gene family, member A GTPase) and Rho kinase ROCK (Rho-associated coiled coil forming protein serine/threonine kinase) inhibiting agent) greatly increased neurite length of the human model neurons while activation of RhoA/ROCK result in growth cone collapse followed by the inhibition of neurite growth.
We and others revealed a pivotal role for RhoA (Ras homolog gene family, member A GTPase) and the Rho kinase ROCK (Rho-associated coiled coil forming protein serine/threonine kinase) signaling on neurite outgrowth of neurons (Boomkamp et al., 2012; DeGeer and Lamarche-Vane, 2013; Tönges et al., 2011; Wu et al., 2009).
Treatment with RhoA/ROCK inhibiting agents increased neurite length of the human
30 Discussion
model neurons (Roloff et al., 2015). Moreover, activation of RhoA caused cytoskeletal changes eventually leading to a growth cone collapse and suppression of axonal re-extension (Gallo and Letourneau, 2004). Since PKG, which is activated downstream the NO/cGMP cascade, regulates the expression and phosphorylation of RhoA (Sauzeau et al., 2003), it is possible that reactive microglia mediate their harmful effects via NO/cGMP/PKG - RhoA/ROCK activation (Fig. 8).
There are, however, also indications that NO-initiated growth cone collapse, axon retraction and reconfiguration of axonal microtubules are not mediated via cGMP/PKG (Ernst et al., 2000; He et al., 2002; Hess et al., 1993). A key event in NO signaling to the axonal cytoskeleton is triggered through the S-nitrosylation of the microtubule-associated protein 1B (MAP1B) (Stroissnigg et al., 2007) which is highly expressed during development and regeneration (Gordon-Weeks and Fischer, 2000;
Soares et al., 2002). S-nitrosylation of MAP1B increases its microtubule binding and inhibits dynein actions leading to a reduction of neurite extension force (Stroissnigg et al., 2007)
Even though microglia-mediated neurite outgrowth inhibition is thought to be partially responsible for the limited axonal recovery, it may initially be advantageous to prevent the ingrowth of neuronal processes into the hostile environment of wounded nervous tissue. Manipulation of microglial activation might thus offer a potential pharmacological target for controlling neuronal repair under acute inflammatory/traumatic conditions, but the exact time frame for a potential treatment has to be carefully evaluated (Block and Hong, 2005; Block et al., 2007; Greter and Merad, 2013; Rock and Peterson, 2006; Scheiblich and Bicker, 2015a).
Conclusion 31
Conclusion
This thesis describes the interrelationship between NO and CO in regulating cellular characteristics of microglia under basal conditions and after activation. For reasons of reducing animal consumption in research the BV-2 cell line was introduced as model system for primary microglia in functional assays. Our experiments on microglial activation, cell migration, phagocytosis of neuronal fragment, and the impact of microglia on neurite outgrowth of human model neurons contribute to better understand the signaling pathways underlying microglial modulation in pathogenic conditions (Fig. 9). Moreover, results of the present thesis support a therapeutic potential of NO synthesis blocking agents and CO-releasing molecules (CORMs) to medicate excessive inflammation within the CNS and to control the inflammatory responsiveness of reactive microglia.
Figure 9: Summary of the key findings of the present thesis. Cellular characteristics of microglia (green), including activation, migration, phagocytosis, and the impact on neurite outgrowth of human model neurons (magenta), are dually regulated by antagonistic interacting nitric oxide (NO) and carbon monoxide (CO) signal transduction pathways.
32 References
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