Neuronal apoptosis suppression and efficient apoptotic cell clearance are crucial for preventing secondary spinal cord injury (SCI). The immunoreceptor CD300a is a phosphatidylserine receptor expressed on myeloid cells that modulates secondary neuronal damage by regulating efferocytosis. CD300a blockade has previously enhanced efferocytosis and improved neurological deficits in an ischemic stroke mouse model. However, the mechanisms and roles of CD300a in acute SCI remain unclear. Therefore, we evaluated the effects of CD300a regulation on acute SCI. First, an SCI model was created in CD300a-deficient mice and compared with that in wild-type mice. Second, we compared the effects of treating wild-type mice with anti-CD300a or control antibodies. The effects were evaluated over 6 weeks by analyzing behavioral outcomes using the Basso Mouse Scale and injured spinal cord tissue. Damage-associated molecular patterns (DAMPs) were evaluated in the acute phase, and oligodendrocyte apoptosis was assessed in the subacute phase of SCI to assess the effects of CD300a on inflammation and secondary injury. CD300a-deficient mice exhibited improved motor function, a reduced lesion area, and an increased residual myelin area. Immunohistochemical staining revealed reduced scarring and more surviving neurons. CD300a-deficient mice exhibited decreased extracellular DAMPs and oligodendrocyte apoptosis in the acute and subacute phases, respectively. The antibody-treated group also exhibited improved motor function, reduced lesion area, and increased residual myelin. These findings suggest that CD300a regulation mitigates SCI by suppressing DAMP release and apoptosis, thereby contributing to reduced tissue damage and functional recovery. These findings highlight CD300a regulation as a potentially effective treatment for acute SCI.
AckeryA, TatorC, KrassioukovA. A global perspective on spinal cord injury epidemiology. J Neurotrauma, 2004; 21(10):1355–1370; doi: 10.1089/neu.2004.21.1355
4.
ChamberlainJD, MeierS, MaderL, et al.Mortality and longevity after a spinal cord injury: Systematic review and meta-analysis. Neuroepidemiology, 2015; 44(3):182–198; doi: 10.1159/000382079
5.
SteinDM, PinedaJA, RoddyV, et al.Emergency neurological life support: Traumatic spine injury. Neurocrit Care, 2015; 23(Suppl 2):S155–S164; doi: 10.1007/s12028-015-0169-y
6.
OkuwakiS, FunayamaT, KodaM, et al.Characteristics of the cervical spine and cervical cord injuries in older adults with cervical ossification of the posterior longitudinal ligament. Sci Rep, 2023; 13(1):2689; doi: 10.1038/s41598-023-29877-2
7.
GBD 2016 Traumatic Brain Injury and Spinal Cord Injury Collaborators. Global, regional, and national burden of traumatic brain injury and spinal cord injury, 1990-2016: A systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol, 2019; 18(1):56–87; doi: 10.1016/S1474-4422(18)30415-0
8.
SternerRC, SternerRM. Immune response following traumatic spinal cord injury: Pathophysiology and therapies. Front Immunol, 2022; 13:1084101; doi: 10.3389/fimmu.2022.1084101
9.
OkadaS. The pathophysiological role of acute inflammation after spinal cord injury. Inflamm Regen, 2016; 36:20; doi: 10.1186/s41232-016-0026-1
10.
MartinonF, BurnsK, TschoppJ. The inflammasome: A molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell, 2002; 10(2):417–426; doi: 10.1016/s1097-2765(02)00599-3
11.
MoY, ChenK. Review: The role of HMGB1 in spinal cord injury. Front Immunol, 2022; 13:1094925; doi: 10.3389/fimmu.2022.1094925
12.
ChenL, DengH, CuiH, et al.Inflammatory responses and inflammation-associated diseases in organs. Oncotarget, 2018; 9(6):7204–7218; doi: 10.18632/oncotarget.23208
13.
KigerlKA, PopovichPG. Toll-like receptors in spinal cord injury. Curr Top Microbiol Immunol, 2009; 336:121–136; doi: 10.1007/978-3-642-00549-7_7
14.
LytleJM, WrathallJR. Glial cell loss, proliferation and replacement in the contused murine spinal cord. Eur J Neurosci, 2007; 25(6):1711–1724; doi: 10.1111/j.1460-9568.2007.05390.x
15.
CroweMJ, BresnahanJC, ShumanSL, et al.Apoptosis and delayed degeneration after spinal cord injury in rats and monkeys. Nat Med, 1997; 3(1):73–76; doi: 10.1038/nm0197-73
16.
WardenP, BamberNI, LiH, et al.Delayed glial cell death following wallerian degeneration in white matter tracts after spinal cord dorsal column Cordotomy in adult rats. Exp Neurol, 2001; 168(2):213–224; doi: 10.1006/exnr.2000.7622
MotheAJ, TatorCH. Advances in stem cell therapy for spinal cord injury. J Clin Invest, 2012; 122(11):3824–3834; doi: 10.1172/JCI64124
19.
BrackenMB, ShepardMJ, CollinsWF, et al.A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury. Results of the second national acute spinal cord injury study. N Engl J Med, 1990; 322(20):1405–1411; doi: 10.1056/NEJM199005173222001
20.
BrackenMB, ShepardMJ, HolfordTR, et al.Administration of methylprednisolone for 24 or 48 hours or Tirilazad Mesylate for 48 hours in the treatment of acute spinal cord injury. Results of the third national acute spinal cord injury randomized controlled trial. National acute spinal cord injury study. JAMA, 1997; 277(20):1597–1604; doi: 10.1001/jama.1997.03540440031029
21.
PollardME, AppleDF. Factors associated with improved neurologic outcomes in patients with incomplete tetraplegia. Spine (Phila Pa 1976), 2003; 28(1):33–39; doi: 10.1097/00007632-200301010-00009
22.
PointillartV, PetitjeanME, WiartL, et al.Pharmacological therapy of spinal cord injury during the acute phase. Spinal Cord, 2000; 38(2):71–76; doi: 10.1038/sj.sc.3100962
23.
HurlbertRJ. Methylprednisolone for acute spinal cord injury: An inappropriate standard of care. J Neurosurg, 2000; 93(1 Suppl):1–7; doi: 10.3171/spi.2000.93.1.0001
24.
MatsumotoT, TamakiT, KawakamiM, et al.Early complications of high-dose methylprednisolone sodium succinate treatment in the follow-up of acute cervical spinal cord injury. Spine (Phila Pa 1976), 2001; 26(4):426–430; doi: 10.1097/00007632-200102150-00020
25.
FehlingsMG, MoghaddamjouA, HarropJS, et al.Safety and efficacy of Riluzole in acute spinal cord injury study (RISCIS): A multi-center, randomized, placebo-controlled, double-blinded trial. J Neurotrauma, 2023; 40(17–18):1878–1888; doi: 10.1089/neu.2023.0163
26.
KodaM, HanaokaH, FujiiY, et al.Randomized trial of granulocyte colony-stimulating factor for spinal cord injury. Brain, 2021; 144(3):789–799; doi: 10.1093/brain/awaa466
27.
AlibaiE, ZandF, RahimiA, et al.Erythropoietin plus methylprednisolone or methylprednisolone in the treatment of acute spinal cord injury: A preliminary report. Acta Med Iran, 2014; 52(4):275–279.
28.
CostaDD, BeghiE, CarignanoP, et al.Tolerability and efficacy of erythropoietin (EPO) treatment in traumatic spinal cord injury: A preliminary randomized comparative trial vs. methylprednisolone (MP). Neurol Sci, 2015; 36(9):1567–1574; doi: 10.1007/s10072-015-2182-5
29.
FehlingsMG, ChenY, AarabiB, et al.A randomized controlled trial of local delivery of a rho inhibitor (VX-210) in patients with acute traumatic cervical spinal cord injury. J Neurotrauma, 2021; 38(15):2065–2072; doi: 10.1089/neu.2020.7096
30.
MaynardG, KannanR, LiuJ, et al.Soluble Nogo-Receptor-Fc decoy (AXER-204) in patients with chronic cervical spinal cord injury in the USA: A first-in-human and randomised clinical trial. Lancet Neurol, 2023; 22(8):672–684; doi: 10.1016/S1474-4422(23)00215-6
31.
ShibuyaA, Nakahashi-OdaC, Tahara-HanaokaS. Regulation of immune responses by the activating and inhibitory myeloid-associate immunoglobulinE-like receptors (MAIR) (CD300). Immune Netw, 2009; 9(2):41–45; doi: 10.4110/in.2009.9.2.41
32.
YotsumotoK, OkoshiY, ShibuyaK, et al.Paired activating and inhibitory immunoglobulin-like receptors, MAIR-I and MAIR-II, regulate mast cell and macrophage activation. J Exp Med, 2003; 198(2):223–233; doi: 10.1084/jem.20021825
33.
AlvarezY, TangX, ColiganJE, et al.The CD300a (IRp60) inhibitory receptor is rapidly up-regulated on human neutrophils in response to inflammatory stimuli and modulates CD32a (FcgammaRIIa) mediated signaling. Mol Immunol, 2008; 45(1):253–258; doi: 10.1016/j.molimm.2007.05.006
34.
JuX, ZenkeM, HartDNJ, et al.CD300a/c regulate type I interferon and TNF-alpha secretion by human plasmacytoid dendritic cells stimulated with TLR7 and TLR9 ligands. Blood, 2008; 112(4):1184–1194; doi: 10.1182/blood-2007-12-127951
35.
Nakahashi-OdaC, Tahara-HanaokaS, HondaS, et al.Identification of phosphatidylserine as a ligand for the CD300a immunoreceptor. Biochem Biophys Res Commun, 2012; 417(1):646–650; doi: 10.1016/j.bbrc.2011.12.025
36.
Nakahashi-OdaC, FujiyamaS, NakazawaY, et al.CD300a blockade enhances efferocytosis by infiltrating myeloid cells and ameliorates neuronal deficit after ischemic stroke. Sci Immunol, 2021; 6(64):eabe7915; doi: 10.1126/sciimmunol.abe7915
37.
UdayangaKGS, NakamuraY, Nakahashi-OdaC, et al.Immunoreceptor CD300a on mast cells and dendritic cells regulates neutrophil recruitment in a murine model of sepsis. Int Immunol, 2016; 28(12):611–615; doi: 10.1093/intimm/dxw047
38.
BassoDM, FisherLC, AndersonAJ, et al.Basso Mouse Scale for locomotion detects differences in recovery after spinal cord injury in five common mouse strains. J Neurotrauma, 2006; 23(5):635–659; doi: 10.1089/neu.2006.23.635
39.
PivettaE, CapuanoA, ScanzianiE, et al.Multiplex staining depicts the immune infiltrate in colitis-induced colon cancer model. Sci Rep, 2019; 9(1):12645; doi: 10.1038/s41598-019-49164-3
40.
WangY, Nakahashi-OdaC, OkayamaY, et al.Autonomous regulation of IgE-mediated mast cell degranulation and immediate hypersensitivity reaction by an inhibitory receptor CD300a. J Allergy Clin Immunol, 2019; 144(1):323–327.e7; doi: 10.1016/j.jaci.2019.03.005
41.
ClarkGJ, JuX, TateC, et al.The CD300 family of molecules are evolutionarily significant regulators of leukocyte functions. Trends Immunol, 2009; 30(5):209–217; doi: 10.1016/j.it.2009.02.003
42.
ClarkGJ, JuX, AzlanM, et al.The CD300 molecules regulate monocyte and dendritic cell functions. Immunobiology, 2009; 214(9–10):730–736; doi: 10.1016/j.imbio.2009.06.004
43.
ZenarruzabeitiaO, VitalléJ, EguizabalC, et al.The biology and disease relevance of CD300a, an inhibitory receptor for phosphatidylserine and phosphatidylethanolamine. J Immunol, 2015; 194(11):5053–5060; doi: 10.4049/jimmunol.1500304
44.
ChengJ, WangW, XiaY, et al.Regulators of phagocytosis as pharmacologic targets for stroke treatment. Front Pharmacol, 2023; 14:1122527; doi: 10.3389/fphar.2023.1122527
45.
ZhangJ, TakahashiHK, LiuK, et al.Anti-high mobility group box-1 monoclonal antibody protects the blood-brain barrier from ischemia-induced disruption in rats. Stroke, 2011; 42(5):1420–1428; doi: 10.1161/STROKEAHA.110.598334
46.
KigerlKA, LaiW, WallaceLM, et al.High mobility group box-1 (HMGB1) is increased in injured mouse spinal cord and can elicit neurotoxic inflammation. Brain Behav Immun, 2018; 72:22–33; doi: 10.1016/j.bbi.2017.11.018
47.
AuAK, AnejaRK, BellMJ, et al.Cerebrospinal fluid levels of high-mobility group box 1 and cytochrome C predict outcome after pediatric traumatic brain injury. J Neurotrauma, 2012; 29(11):2013–2021; doi: 10.1089/neu.2011.2171
48.
LairdMD, ShieldsJS, Sukumari-RameshS, et al.High mobility group box protein-1 promotes cerebral edema after traumatic brain injury via activation of toll-like receptor 4. Glia, 2014; 62(1):26–38; doi: 10.1002/glia.22581
49.
ChenKB, UchidaK, NakajimaH, et al.High-mobility group box-1 and its receptors contribute to proinflammatory response in the acute phase of spinal cord injury in rats. Spine (Phila Pa 1976), 2011; 36(25):2122–2129; doi: 10.1097/BRS.0b013e318203941c
50.
SuyamaK, WatanabeM, SakaiD, et al.Nkx2.2 expression in differentiation of oligodendrocyte precursor cells and inhibitory factors for differentiation of oligodendrocytes after traumatic spinal cord injury. J Neurotrauma, 2007; 24(6):1013–1025; doi: 10.1089/neu.2006.0151
51.
WatanabeM, ToyamaY, NishiyamaA. Differentiation of proliferated NG2-positive glial progenitor cells in a remyelinating lesion. J Neurosci Res, 2002; 69(6):826–836; doi: 10.1002/jnr.10338
52.
LeeY, MorrisonBM, LiY, et al.Oligodendroglia metabolically support axons and contribute to neurodegeneration. Nature, 2012; 487(7408):443–448; doi: 10.1038/nature11314
53.
ShafqatA, AlbalkhiI, MagablehHM, et al.Tackling the glial scar in spinal cord regeneration: New discoveries and future directions. Front Cell Neurosci, 2023; 17:1180825; doi: 10.3389/fncel.2023.1180825
54.
PukosN, GoodusMT, SahinkayaFR, et al.Myelin status and oligodendrocyte lineage cells over time after spinal cord injury: What do we know and what still needs to be unwrapped? Glia, 2019; 67(11):2178–2202; doi: 10.1002/glia.23702
55.
PukosN, MarionCM, ArnoldWD, et al.Chronic demyelination and myelin repair after spinal cord injury in mice: A potential link for glutamatergic axon activity. Glia, 2023; 71(9):2096–2116; doi: 10.1002/glia.24382
