The Complement Receptor C5aR Controls Acute Inflammation and Astrogliosis following Spinal Cord Injury.

This study investigated the role of the complement activation fragment C5a in secondary pathology following contusive spinal cord injury (SCI). C5ar(-/-) mice, which lack the signaling receptor for C5a, displayed signs of improved locomotor recovery and reduced inflammation during the first week of SCI compared with wild-type mice. Intriguingly, the early signs of improved recovery in C5ar(-/-) mice deteriorated from day 14 onward, with absence of C5aR ultimately leading to poorer functional outcomes, larger lesion volumes, reduced myelin content, and more widespread inflammation at 35 d SCI. Pharmacological blockade of C5aR with a selective antagonist (C5aR-A) during the first 7 d after SCI improved recovery compared with vehicle-treated mice, and this phenotype was sustained up to 35 d after injury. Consistent with observations made in C5ar(-/-) mice, these improvements were, however, lost if C5aR-A administration was continued into the more chronic phase of SCI. Signaling through the C5a-C5aR axis thus appears injurious in the acute period but serves a protective and/or reparative role in the post-acute phase of SCI. Further experiments in bone marrow chimeric mice suggested that the dual and opposing roles of C5aR on SCI outcomes primarily relate to its expression on CNS-resident cells and not infiltrating leukocytes. Additional in vivo and in vitro studies provided direct evidence that C5aR signaling is required during the postacute phase for astrocyte hyperplasia, hypertrophy, and glial scar formation. Collectively, these findings highlight the complexity of the inflammatory response to SCI and emphasize the importance of optimizing the timing of therapeutic interventions.

Genetic or Pharmacological Ablation of Acid-Sensing Ion Channel 1a (ASIC1a) Is Not Neuroprotective in a Mouse Model of Spinal Cord Injury.

Acid-sensing ion channel 1a (ASIC1a) is a proton-activated channel that is expressed ubiquitously throughout the central nervous system and in various types of immune cells. Its role in spinal cord injury (SCI) is controversial; inhibition of ASIC1a has been reported to improve SCI pathology in vivo, but conversely, gene ablation increased kainite-mediated excitotoxic cell death in vitro. Here, we re-examined the role of ASIC1a in a mouse model of SCI. First, we observed functional outcomes up to 42 days post-operation (DPO) in SCI mice with a selective genetic ablation of ASIC1a. Mice lacking ASIC1a had significantly worsened locomotor ability and increased lesion size compared with mice possessing the ASIC1a gene. Next, we explored pharmacological antagonism of this ion channel by administering the potent ASIC1a inhibitor, Hi1a. Consistent with a role for ASIC1a to attenuate excitotoxicity, accelerated neuronal cell loss was found at the lesion site in SCI mice treated with Hi1a, but there were no differences in locomotor recovery. Moreover, ASIC1a inhibition did not cause significant alterations to neutrophil migration, microglial density, or blood-spinal cord barrier integrity.

Mobilisation of the splenic monocyte reservoir and peripheral CX3CR1 deficiency adversely affects recovery from spinal cord injury.

Macrophages in the injured spinal cord originate from resident microglia and blood monocytes. Whether this diversity in origins contributes to their seemingly dual role in immunopathology and repair processes has remained poorly understood. Here we took advantage of Cx3cr1(gfp) mice to visualise monocyte-derived macrophages in the injured spinal cord via adoptive cell transfer and bone marrow (BM) chimera approaches. We show that the majority of infiltrating monocytes at 7 days post-injury originate from the spleen and only to a lesser extent from the BM. Prevention of early monocyte infiltration via splenectomy was associated with improved recovery at 42 days post-SCI. In addition, an increased early presence of infiltrating monocytes/macrophages, as a result of CX3CR1 deficiency within the peripheral immune compartment, correlated with worsened injury outcomes. Adoptive transfer of identified Cx3cr1(gfp/+) monocytes confirmed peak infiltration at 7 days post-injury, with inflammatory (Ly6C(high)) monocytes being most efficiently recruited. Focal SCI also changed the composition of the two major monocyte subsets in the blood, with more Ly6C(high) cells present during peak recruitment. Adoptive transfer experiments further suggested high turnover of inflammatory monocytes in the spinal cord at 7 days post-injury. Consistent with this, only a small proportion of infiltrating cells unequivocally expressed polarisation markers for pro-inflammatory (M1) or alternatively activated (M2) macrophages at this time point. Our findings offer new insights into the origins of monocyte-derived macrophages after SCI and their contribution to functional recovery, providing a basis for further scrutiny and selective targeting of Ly6C(high) monocytes to improve outcomes from neurotraumatic events.