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Targeted Modulation of the Neuroinflammatory Response after Spinal Cord Injury

The Ongoing Quest for the “Holy Grail”
  • Philip F. Stahel
    Correspondence
    Address reprint requests to Philip F. Stahel, M.D., F.A.C.S., Department of Orthopaedic Surgery and Department of Neurosurgery, University of Colorado Denver, School of Medicine Denver Health Medical Center, 777 Bannock Street, Denver, CO 80204
    Affiliations
    Departments of Orthopaedic Surgery and Neurosurgery, University of Colorado Denver, School of Medicine, Denver Health Medical Center, Denver, Colorado
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  • Michael A. Flierl
    Affiliations
    Departments of Orthopaedic Surgery and Neurosurgery, University of Colorado Denver, School of Medicine, Denver Health Medical Center, Denver, Colorado
    Search for articles by this author
      This Commentary discusses the role of inflammation after spinal cord injury.
      Healing of the injured spinal cord represents one of the remaining challenging frontiers in medicine. The posttraumatic neuroinflammatory response has been shown to contribute, at least in part, to the development of secondary neuronal cell death.
      • Chan CC
      Inflammation: beneficial or detrimental after spinal cord injury?.
      Research strategies to prevent these pathological sequelae after spinal cord injury (SCI) have largely failed in translation from the “bench to beside.”
      • Buchli AD
      • Rouiller E
      • Mueller R
      • Dietz V
      • Schwab ME
      Repair of the injured spinal cord: a joint approach of basic and clinical research.
      A classic example related to our lack of understanding the basic immunological mechanisms that lead to delayed neuronal cell death is the failure to administer high-dose methylprednisolone to improve neurological outcome after SCI.
      • Hurlbert RJ
      Methylprednisolone for acute spinal cord injury: an inappropriate standard of care.
      While considered a standard of care incorporated in clinical guidelines for many years, based on promising data from the NASCIS trials, high-dose steroids recently were recognized to be harmful, rather than beneficial, in the management of acute SCI, and their application in the field of neurotrauma is now considered obsolete.
      • Sauerland S
      • Maegele M
      A CRASH landing in severe head injury.
      • Kortbeek JB
      • Al Turki SA
      • Ali J
      • Antoine JA
      • Bouillon B
      • Brasel K
      • Brenneman F
      • Brink PR
      • Brohi K
      • Burris D
      • Burton RA
      • Chapleau W
      • Cioffi W
      • Collet e Silva Fde S
      • Cooper A
      • Cortes JA
      • Eskesen V
      • Fildes J
      • Gautam S
      • Gruen RL
      • Gross R
      • Hansen KS
      • Henny W
      • Hollands MJ
      • Hunt RC
      • Jover Navalon JM
      • Kaufmann CR
      • Knudson P
      • Koestner A
      • Kosir R
      • Larsen CF
      • Livaudais W
      • Luchette F
      • Mao P
      • McVicker JH
      • Meredith JW
      • Mock C
      • Mori ND
      • Morrow C
      • Parks SN
      • Pereira PM
      • Pogetti RS
      • Ravn J
      • Rhee P
      • Salomone JP
      • Schipper IB
      • Schoettker P
      • Schreiber MA
      • Smith RS
      • Svendsen LB
      • Taha W
      • van Wijngaarden-Stephens M
      • Varga E
      • Voiglio EJ
      • Williams D
      • Winchell RJ
      • Winter R
      Advanced trauma life support, edition 8: the evidence for change.
      • Hurlbert RJ
      • Hamilton MG
      Methylprednisolone for acute spinal cord injury: 5-year practice reversal.
      Current research strategies in neurotrauma are therefore aimed at targeting more specific pathways of inflammation, such as the pharmacological inhibition of the complement cascade, which represents the major effector arm of the innate immune system.
      • Stahel PF
      • Barnum SR
      The role of the complement system in CNS inflammatory diseases.
      Interestingly, the first studies investigating complement activation in patients with SCI were published more than three decades ago. In 1980, Rebhuhn and Botvin
      • Rebhuhn J
      • Botvin J
      Complement elevation in spinal cord injury.
      showed that about two-thirds of all patients with SCI had elevated complement levels, and the authors postulated that complement activation may propagate a “self-feeding” immunological response responsible for the failure of regeneration of the injured spinal cord. The recent availability of higher quality complement reagents, including genetically engineered mice and tissue-targeted chimeric complement inhibitors, currently allows for the more detailed elucidation of specific pathways of complement activation involved in the pathophysiology of neuroinflammation after SCI
      • Stahel PF
      • Barnum SR
      The role of the complement system in CNS inflammatory diseases.
      • Qiao F
      • Atkinson C
      • Song H
      • Pannu R
      • Singh I
      • Tomlinson S
      Complement plays an important role in spinal cord injury and represents a therapeutic target for improving recovery following trauma.
      (Figure 1).
      Figure thumbnail gr1
      Figure 1Simplified depiction of the three traditional complement activation pathways and the potential pharmacological interventions designed to ameliorate the extent of neuroinflammation and neuropathology after spinal cord injury. See text for details.
      The recent study by Qiao and colleagues
      • Qiao F
      • Atkinson C
      • Shunmugavel A
      • Morgan BP
      • Song H
      • Tomlinson S
      The alternative and terminal pathways of complement mediate post-traumatic spinal cord inflammation and injury.
      published in this issue of The American Journal of Pathology was designed to analyze the role of the alternative activation pathway (factor B) and terminal lytic pathway (C5b-9) in contributing to the secondary neuropathological sequelae after traumatic SCI in adult C57BL/6 mice.
      • Qiao F
      • Atkinson C
      • Shunmugavel A
      • Morgan BP
      • Song H
      • Tomlinson S
      The alternative and terminal pathways of complement mediate post-traumatic spinal cord inflammation and injury.
      In the first part of the study, a traumatic spinal cord contusion was applied to mice with a genetic deficiency for factor B (fB−/−). These mice therefore lacked a functional alternative pathway of complement activation.
      • Leinhase I
      • Holers VM
      • Thurman JM
      • Harhausen D
      • Schmidt OI
      • Pietzcker M
      • Taha ME
      • Rittirsch D
      • Huber-Lang M
      • Smith WR
      • Ward PA
      • Stahel PF
      Reduced neuronal cell death after experimental brain injury in mice lacking a functional alternative pathway of complement activation.
      Impressively, fB−/− mice showed significantly improved locomotor function scores for up to 21 days after trauma, compared to wild-type controls. The neurological improvement was substantiated by significantly reduced neutrophil infiltration, complement deposition, and tissue damage in the injured spinal cord of fB−/− mice, compared to that of wild-type littermates. These data imply a crucial role of complement activation, via the alternative pathway, in the development of posttraumatic neuroinflammation and propagation of delayed neuronal injury. In the second part of the study, these positive insights derived from gene knockout mice were translated to a pharmacological approach using a neutralizing monoclonal anti-factor B antibody (mAb1379), which is a potent inhibitor of the alternative complement activation pathway.
      • Thurman JM
      • Kraus DM
      • Girardi G
      • Hourcade D
      • Kang HJ
      • Royer PA
      • Mitchell LM
      • Giclas PC
      • Salmon J
      • Gilkeson G
      • Holers VM
      A novel inhibitor of the alternative complement pathway prevents antiphospholipid antibody-induced pregnancy loss in mice.
      • Leinhase I
      • Rozanski M
      • Harhausen D
      • Thurman JM
      • Schmidt OI
      • Hossini AM
      • Taha ME
      • Rittirsch D
      • Ward PA
      • Holers VM
      • Ertel W
      • Stahel PF
      Inhibition of the alternative complement activation pathway in traumatic brain injury by a monoclonal anti-factor B antibody: a randomized placebo-controlled study in mice.
      Using a clinically relevant paradigm of systemic (intravenous) compound administration at 1 and 12 hours after trauma, the authors were able to replicate the neuroprotective effects seen in fB−/− mice, to the pharmacological mAb1379-treatment model in wild-type mice, using vehicle-injected animals as appropriate controls. Finally, the third part of the study was designed to determine the role of the membrane attack complex (C5b-9), as the terminal downstream event of complement activation, in the neuropathophysiology after SCI. For this purpose, mice lacking the gene for the membrane-bound complement regulatory molecule CD59a (CD59a−/−) were subjected to traumatic spinal cord injury and analyzed by the same outcome parameters as for the fB−/− mice. One of the putative mechanisms of complement-mediated neuronal death after spinal cord injury is represented by posttraumatic activation of phosphatidyl inositol-specific phospholipase C (PI-PLC), which renders neurons vulnerable to membrane attack complex-mediated lysis by shedding of the glycosyl phosphatidyl inositol-anchored glycoprotein CD59a from neuronal membranes.
      • Stahel PF
      • Morganti-Kossmann MC
      • Kossmann T
      The role of the complement system in traumatic brain injury.
      • Morgan BP
      Regulation of the complement membrane attack pathway.
      In contrast with data from fB−/− mice and mAb1379-treated animals, CD59a−/− mice showed a significant deterioration of neurological scores from 11 to 21 days after SCI, compared to wild-type littermates. In addition, deposition of complement C9, as a surrogate marker for the membrane attack complex (C5b-9), was significantly increased in the spinal cord of CD59a−/− mice and associated with exacerbated tissue damage and local neutrophil infiltration.
      • Qiao F
      • Atkinson C
      • Shunmugavel A
      • Morgan BP
      • Song H
      • Tomlinson S
      The alternative and terminal pathways of complement mediate post-traumatic spinal cord inflammation and injury.
      The exact cellular and molecular mechanisms of complement-mediated neuropathology after spinal cord injury remain far from fully understood. The present study
      • Qiao F
      • Atkinson C
      • Shunmugavel A
      • Morgan BP
      • Song H
      • Tomlinson S
      The alternative and terminal pathways of complement mediate post-traumatic spinal cord inflammation and injury.
      sheds further light toward our understanding of the immunological pathophysiology of SCI, as it offers novel insights into the impact of the different complement activation pathways (classical, alternative, lectin, and terminal pathway) and their involvement in posttraumatic neuroinflammation and neurodegeneration
      • Anderson AJ
      • Robert S
      • Huang W
      • Young W
      • Cotman CW
      Activation of complement pathways after contusion-induced spinal cord injury.
      • Reynolds DN
      • Smith SA
      • Zhang YP
      • Mengsheng Q
      • Lahiri DK
      • Morassutti DJ
      • Shields CB
      • Kotwal GJ
      Vaccinia virus complement control protein reduces inflammation and improves spinal cord integrity following spinal cord injury.
      (Figure 1).
      Recent experimental studies have provided initial evidence of involvement of the classical pathway of complement activation in the pathogenesis of neuronal tissue damage and adverse neurological outcome after SCI.
      • Galvan MD
      • Luchetti S
      • Burgos AM
      • Nguyen HX
      • Hooshmand MJ
      • Hamers FP
      • Anderson AJ
      Deficiency in complement C1q improves histological and functional locomotor outcome after spinal cord injury.
      In contrast, data from multiple studies on inflammatory conditions in and outside the CNS have revealed that the selective inhibition of the alternative complement pathway may represent a promising new immunomodulatory approach for multiple neuroinflammatory disorders.
      • Stahel PF
      • Barnum SR
      The role of the complement system in CNS inflammatory diseases.
      • Leinhase I
      • Holers VM
      • Thurman JM
      • Harhausen D
      • Schmidt OI
      • Pietzcker M
      • Taha ME
      • Rittirsch D
      • Huber-Lang M
      • Smith WR
      • Ward PA
      • Stahel PF
      Reduced neuronal cell death after experimental brain injury in mice lacking a functional alternative pathway of complement activation.
      • Leinhase I
      • Rozanski M
      • Harhausen D
      • Thurman JM
      • Schmidt OI
      • Hossini AM
      • Taha ME
      • Rittirsch D
      • Ward PA
      • Holers VM
      • Ertel W
      • Stahel PF
      Inhibition of the alternative complement activation pathway in traumatic brain injury by a monoclonal anti-factor B antibody: a randomized placebo-controlled study in mice.
      • Holers VM
      • Thurman JM
      The alternative pathway of complement in disease: opportunities for therapeutic targeting.
      • Thurman JM
      • Holers VM
      The central role of the alternative complement pathway in human disease.
      • Banda NK
      • Thurman JM
      • Kraus D
      • Wood A
      • Carroll MC
      • Arend WP
      • Holers VM
      Alternative complement pathway activation is essential for inflammation and joint destruction in the passive transfer model of collagen-induced arthritis.
      The current experimental study
      • Qiao F
      • Atkinson C
      • Shunmugavel A
      • Morgan BP
      • Song H
      • Tomlinson S
      The alternative and terminal pathways of complement mediate post-traumatic spinal cord inflammation and injury.
      implies that the therapeutic inhibition of the alternative pathway (factor B) during a clinically relevant time window within 1 to 12 hours after trauma may represent a promising new avenue in the search for a pharmacological remedy to host-mediated progressive inflammation and neurodegeneration within the injured spinal cord. In this regard, it is notable that the monoclonal anti-factor B antibody used in the present study has cross-reactivity across species and was originally designed as an anti-human antibody.
      • Thurman JM
      • Kraus DM
      • Girardi G
      • Hourcade D
      • Kang HJ
      • Royer PA
      • Mitchell LM
      • Giclas PC
      • Salmon J
      • Gilkeson G
      • Holers VM
      A novel inhibitor of the alternative complement pathway prevents antiphospholipid antibody-induced pregnancy loss in mice.
      • Leinhase I
      • Rozanski M
      • Harhausen D
      • Thurman JM
      • Schmidt OI
      • Hossini AM
      • Taha ME
      • Rittirsch D
      • Ward PA
      • Holers VM
      • Ertel W
      • Stahel PF
      Inhibition of the alternative complement activation pathway in traumatic brain injury by a monoclonal anti-factor B antibody: a randomized placebo-controlled study in mice.
      Thus, this specific compound has potential for promising “bench-to-bedside” translation in the future. Similarly, the therapeutic blockade of membrane attack complex assembly, by the use of anti-C9 antibodies, or stimulation/up-regulation of CD59 expression (eg, through gene therapy), may represent a new strategy to avoid “innocent bystander” complement-mediated neuronal lysis after spinal cord injury.
      Future experimental studies must be designed to titrate the optimal dosage, time window of administration, and time intervals for repeated injections of these new generation complement inhibitory and regulatory molecules. One shortcoming of these therapeutic approaches is the potential for a limited extent of complement inhibition related to the half-life of these compounds and peak concentration at the site of the injured tissue. In this regard, repeated injections at closer time intervals and the use of newly available chimeric compounds consisting of complement inhibitors fused to complement receptors that bind at the site of complement activation, such as CR2-factor H and CR2-Crry molecules,
      • Qiao F
      • Atkinson C
      • Song H
      • Pannu R
      • Singh I
      • Tomlinson S
      Complement plays an important role in spinal cord injury and represents a therapeutic target for improving recovery following trauma.
      • Banda NK
      • Levitt B
      • Glogowska MJ
      • Thurman JM
      • Takahashi K
      • Stahl GL
      • Tomlinson S
      • Arend WP
      • Holers VM
      Targeted inhibition of the complement alternative pathway with complement receptor 2 and factor H attenuates collagen antibody-induced arthritis in mice.
      may represent the future “golden bullet” for amelioration of complement-mediated exacerbation of SCI.

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      Linked Article

      • The Alternative and Terminal Pathways of Complement Mediate Post-Traumatic Spinal Cord Inflammation and Injury
        The American Journal of PathologyVol. 177Issue 6
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          Complement is implicated in the inflammatory response and the secondary neuronal damage that occurs after traumatic spinal cord injury (SCI). Complement can be activated by the classical, lectin, or alternative pathways, all of which share a common terminal pathway that culminates in formation of the cytolytic membrane attack complex (MAC). Here, we investigated the role of the alternative and terminal complement pathways in SCI. Mice deficient in the alternative pathway protein factor B (fB) were protected from traumatic SCI in terms of reduced tissue damage and demyelination, reduced inflammatory cell infiltrate, and improved functional recovery.
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