Upon injury inflammation is one of the first responses that are triggered. Modulating the inflammatory response may have important consequences to enhance the regenerative capabilities in different systems. Thus, too little or too much inflammation can inhibit or alter processes such us wound healing or cell proliferation that are required for proper repair and regeneration. As previously mentioned in this blog, the failure of mammalian CNS to regenerate depends in great measure on the inhibitory action of myelin and the glial scar. This is also true for the axons of the retinal ganglion cells (RGC), that after optic nerve injury normally die by apoptosis. Previous works have shown that the JAK/STAT3 and PI3K/Akt signalling pathways can enhance the regenerative response of RGC axons. Similar enhancement can be seen after inflammation stimulation, that does not only promote axonal regrowth but also plays a neuroprotective function as it increases the survival rate of RGCs upon injury.
In a recent paper from the laboratory of Dietmar Fischer the authors show how interleukin-6 is an important mediator of RGCs regeneration upon inflammatory stimulation (http://www.nature.com/cddis/journal/v4/n4/abs/cddis2013126a.html) in rats. IL-6 is a cytokine that is lowly expressed in the CNS but strongly upregulated after ischemia, trauma or axotomy in the peripheral nervous system. Here, the authors first show that IL-6 is upregulated in the retina after optic nerve crush or inflammatory stimulation. In retinal cell cultures IL-6 increases neurite growth not only in permissive substrates but also in inhibitory substrates as CNS myelin extracts. Moreover, the presence of a IL-6 antibody in the medium blocks this IL-6-stimulated neurite outgrowth. Also, IL-6 exerts a neuroprotective role on the cultured RGCs, although this effect is lower compared to those exerted by other neuroprotective and axon-promoting factors such as CNTF (astrocyte-derived ciliary neurotrophic factor). Consistent with this function of IL-6, the authors show how a IL-6 receptor is expressed in retinal cells as well as in Müller cells. When cells are cultured with an antibody against IL-6 receptor, the growth-promoting effect of IL-6 is significantly reduced. Also, when this receptor is activated by another cytokine it induces neurite growth at a similar level as IL-6 does. These results indicate that the stimulation of the IL-6 receptor is sufficient to promote neurite growth.
The effects of IL-6 on RGCs regeneration is mediated through the activation of the JAK/STAT3 and PI3K/Akt pathways. Thus, IL-6 promotes the phosphorilation of STAT3 and, on the other side, drug-mediated inhibition of the of these two signalling pathways blocks the regeneration response induced by the treatment with IL-6. Finally, the authors also check the effects of IL-6 in vivo. To do that they injected IL-6 protein after optic nerve crush and saw the activation of the JAK/STAT3 pathway as well as the upregulation of some genes associated to regeneration such as Sprr1a, galanin and gap-43. Retinal cell cultures from rats that went through optic nerve crush and posterior IL-6 injections show a significant increase in neurite outgrowth, suggesting that IL-6 transforms those RGCs into a regenerative state.
In summary, IL-6 is an important element for optic nerve regeneration mediated by inflammatory stimulation. Further studies will be necessary to see up to what extend this system can become a therapeutical target to promote optic nerve regeneration in mammals.