Nervous Immunity – a study on the role of complement system in neuronal degeneration and regeneration – M. Sta
Background: Previous research, showed that during neuronal degeneration the complement system, part of innate immunity, is activated. The complement system is a first line of defense against pathogens, but also plays a role in clearing cellular debris. Upon activation it will target material for phagocytosis, attract phagocytes and generate the membrane attack complex (MAC), a pore forming structure that causes cells to leak. Inhibition of MAC formation resulted in decreased influx of macrophages and a delayed degeneration, but faster recovery after sciatic nerve crush in rats (Ramaglia et. al., 2007, 2008, and 2009).
Results: This study shows that macrophages are responsible for rapid myelin clearance and MAC for rapid axonal degeneration. MAC induces surrounding cells to produce macrophage attracting and activation cytokines. This results in a pro-inflammatory macrophage and T helper cell response. The absence of MAC results in an anti-inflammatory environment and upregulation of genes that promote neurite outgrowth. In nerves, the amount of MAC deposition is dependent on the size of injury. We developed an ex vivo electrophysiology method, which showed onset of regeneration starts at two days after injury (Sta et. al., 2014a). A study with a small nerve crush and low complement level of activation showed that wild type and complement deficient animals have the same intrinsic abilities of nerve regeneration (Sta et. al., 2014b)
Study of the immune system in amyotrophic lateral sclerosis showed that activation of the complement system is observed in all patients. Presence of dendritic cells and CD8 positive T-cells are associated with rapid disease progression, whereas the presence of CD68 positive cells is associated with slow disease progression (Sta et. al., 2011). Toll-like receptors are also activated; the interaction of TLR4 with HMBG1 is a possible cause for selective motor neuron loss (Casula et. al., 2011).
Conclusion: Inhibition of MAC formation is a powerful tool to improve peripheral nerve regeneration after injury or disease, but it is only beneficial when substantial complement activation is observed. One must carefully consider the activation state of the complement system in each given stage of the disease prior to inhibiting the terminal complement activation, MAC formation.
Casula M, Iyer AM, Spliet WG, Anink JJ, Steentjes K, Sta M, Troost D, Aronica E (2011) Toll-like receptor signaling in amyotrophic lateral sclerosis spinal cord tissue. Neuroscience 179:233-243.
Ramaglia V, King RH, Nourallah M, Wolterman R, de Jonge R., Ramkema M, Vigar MA, van der Wetering S, Morgan BP, Troost D, Baas F (2007) The membrane attack complex of the complement system is essential for rapid Wallerian degeneration. J Neurosci 27:7663-7672.
Ramaglia V, Tannemaat MR, de Kok M., Wolterman R, Vigar MA, King RH, Morgan BP, Baas F (2009) Complement inhibition accelerates regeneration in a model of peripheral nerve injury. Mol Immunol 47:302-309.
Ramaglia V, Wolterman R, de Kok M, Vigar MA, Wagenaar-Bos I, King RH, Morgan BP, Baas F (2008) Soluble complement receptor 1 protects the peripheral nerve from early axon loss after injury. Am J Pathol 172:1043-1052.
Sta M, Sylva-Steenland RM, Casula M, de Jong JM, Troost D, Aronica E, Baas F (2011) Innate and adaptive immunity in amyotrophic lateral sclerosis: Evidence of complement activation. Neurobiol Dis.
Sta M, Cappaert NL, Ramekers D, Baas F, Wadman WJ (2014a) The functional and morphological characteristics of sciatic nerve degeneration and regeneration after crush injury in rats. J Neurosci Methods 222:189-198.
Sta M, Cappaert NL, Ramekers D, Ramaglia V, Wadman WJ, Baas F (2014b) C6 deficiency does not alter intrinsic regeneration speed after peripheral nerve crush injury. Neurosci Res.