Delayed post-injury administration of C5a improves regeneration and functional recovery after spinal cord injury in mice

Abstract

SummaryThe activation of a complement system can aggravate the secondary injury after spinal cord injury (SCI). However, it was reported recently that the activation of a complement could have both a secondary injury and a neuroprotective effect, in which C5a is the most important factor, but there is no direct evidence for this dual effect of C5a after SCI. In order to investigate the potential neuroprotective effect of C5a after SCI, in this study ectogenic C5a was injected intraperitoneally before/after SCI in vivo, or administrated to mechanically injured neurones in vitro; following this, neurone apoptosis, neurite outgrowth, axonal regeneration and functional recovery were investigated. The in-vivo experiments indicated that, following treatment with C5a 24 h before or immediately after injury, locomotor function was impaired significantly. However, when treatment with C5a took place 24 h after injury, locomotor function improved significantly. In-vitro experiments indicated that a certain concentration of C5a (50-100 nM) could inhibit caspase-3-mediated neurone apoptosis by binding to its receptor CD88, and that it could even promote the neurite outgrowth of uninjured neurones. In conclusion, delayed post-injury administration of C5a within a certain concentration could exert its neuroprotective effect through inhibiting caspase-3-mediated neurone apoptosis and promoting neurite outgrowth of uninjured neurones as well. These data suggest that C5a may have opposite functions in a time-and concentration-dependent manner after SCI. The dual roles of C5a have to be taken into account when measures are taken to inhibit complement activation in order to promote regeneration after SCI.

New Insights on Complement Inhibitor CD59 in Mouse Laser-Induced Choroidal Neovascularization: Mislocalization After Injury and Targeted Delivery for Protein Replacement

“…In addition, anaphylatoxins have been found to be essential in promoting tissue regeneration and repair in retina and CNS. 49,50 Staining with the C5b-9 antibody illustrated that when CR2-CD59 was administered, MAC was still able to form in the existing, although significantly smaller, wounds (Fig. 4).…”

Regulatory gene network for coffee-like color morph of TYRP1 mutant of oujiang color common carp

“…According to the observation of Clark A., et al [ 42 ], it is suspected that complement C3 became active via plasmin (PLG) and thrombin (F7, F10, F2) proteases in a regenerative response. Regenerative effects of this pathway have also been evident in neurons [ 44 ], osteoblasts [ 45 ], and dental pulp progenitors [ 46 ]. It is, thus, expected that upregulation of C3 from the alternative pathway, C2 from both classical and lectin-dependent complement pathways highly increased the proteolytic cleavage of C3 to form C3b for mediating target clearance and forming C5 to C9 by associating with C3 convertase and finally initiating the assembly of the membrane attack complex as the regenerated cells.…”

The Immune System in Tissue Environments Regaining Homeostasis after Injury: Is “Inflammation” Always Inflammation?

“…In particular, C3a and C5a activated NF- κ B/STAT-3 and enhanced hepatocyte regeneration after liver injury [ 59 ]. Recent reports showed that the delayed postinjury administration of C5a inhibited caspase-3 mediated neuron apoptosis leading to improved regeneration and functional recovery after murine spinal cord injury [ 60 ], as well as administration of C3a retina regeneration via STAT-3 activation in the progenitor cells present in the eye [ 61 ].…”