Can the immune system be harnessed to repair the CNS?

Popovich, Phillip G.; Longbrake, Erin E.

doi:10.1038/nrn2398

Cited by 254 publications

(214 citation statements)

References 287 publications

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“…However, inflammatory responses are complex, and benefits of inflammation to the CNS are increasingly being appreciated (Schwartz and Yoles, 2006;Popovich and Longbrake, 2008). Indeed, in support of our finding for a beneficial role for neutrophil recruitment, others have documented more oxidative stress within the injured cord in the absence of neutrophils (de Castro et al, 2004).…”

Section: Discussionsupporting

confidence: 69%

Depletion of Ly6G/Gr-1 Leukocytes after Spinal Cord Injury in Mice Alters Wound Healing and Worsens Neurological Outcome

Stirling¹,

Liu²,

Kubes³

et al. 2009

J. Neurosci.

204

155

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Spinal cord injury (SCI) induces a robust inflammatory response and the extravasation of leukocytes into the injured tissue. To further knowledge of the functions of neuroinflammation in SCI in mice, we depleted the early arriving neutrophils using an anti-Ly6G/Gr-1 antibody. Complete blood counts revealed that neutrophils increased ϳ3-fold over uninjured controls and peaked at 6 -12 h after injury, and that anti-Ly6G/Gr-1 treatment reduced circulating neutrophils by Ͼ90% at these time points. Intravital and spinning disk confocal microscopy of the exposed posterior vein and postcapillary venules showed a significant reduction in rolling and adhering neutrophils in vivo after anti-Ly6G/Gr-1 treatment; this was accompanied by a parallel reduction in neutrophil numbers within the injured spinal cord at 24 and 48 h as determined by flow cytometry. The evolution of astrocyte reactivity, a wound healing response, was reduced in anti-Ly6G/Gr-1-treated mice, which also had less spared white matter and axonal preservation compared with isotype controls. These histological outcomes may be caused by alterations of growth factors and chemokines important in promoting wound healing. Importantly, anti-Ly6G/Gr-1 treatment worsened behavioral outcome as determined using the Basso Mouse Scale and subscores. Although the spectrum of cells affected by anti-Ly6G/Gr-1 antibody treatment cannot be fully ascertained at this point, the correspondence of neutrophil depletion and worsened recovery suggests that neutrophils promote recovery after SCI through wound healing and protective events that limit lesion propagation.

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Section: Discussionsupporting

confidence: 69%

Depletion of Ly6G/Gr-1 Leukocytes after Spinal Cord Injury in Mice Alters Wound Healing and Worsens Neurological Outcome

Stirling¹,

Liu²,

Kubes³

et al. 2009

J. Neurosci.

204

155

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“…8 Recent studies have demonstrated that sCD95L promotes an autoimmune reaction; 21 however, it is still unclear whether autoimmune reactions are beneficial or if a 'protective autoimmunity' exists. 22 In other words, there is not enough evidence to suggest that mCD95L is associated with neurological damage and sCD95L is associated with beneficial processes following SCI. Nevertheless, this is an interesting question and we hope that researchers will pursue it in future studies.…”

Section: Discussionmentioning

confidence: 99%

Increase in soluble CD95L during subacute phases after human spinal cord injury: a potential therapeutic target

et al. 2012

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Study design: A pilot study measuring the levels of serum-soluble CD95 ligand (CD95L) in eight spinal cord-injured patients. Objectives: To determine the soluble concentration of CD95L in spinal cord injury (SCI) patients after trauma. Methods: We collected blood samples from eight patients with acute traumatic SCI. Soluble CD95L serum levels were determined using an enzyme-linked immunosorbent assay. American Spinal Injury Association (ASIA) was determined according to ASIA classification. The patients were monitored, and venous blood was drawn after arrival at the hospital on the 1st and 3rd day and during the 1st, 2nd, 4th, 8th and 12th weeks after trauma. Results: The average patient age was 48.1 years (18-86 years). Three patients were paraplegic (two incomplete, one complete), five were quadriplegic (one complete, four incomplete). The serum concentration of soluble CD95L (sCD95L) decreased during the 1st week (41 ng l À1 ) and increased after the 2nd week in all eight patients. It peaked during the 4th week (68.5 ng l À1 ) and reached a plateau during the 12th week (76.2 ng l À1 ). There are many possible explanations for not being able to detect a statistical significance, one of course being the small sample size. Conclusion: Promising results for anti-CD95L therapy have already been documented in lab studies with rodents. Anti-CD95L blocks the pro-apoptotic and proinflammatory activity of membrane-bound CD95L during the acute phase of SCI. We observed that sCD95L levels are elevated during the subacute and intermediate phases of SCI. It would be of great interest to study a larger group of patients to determine whether higher sCD95 levels are correlated with improved or impaired neurological outcome or with increasing levels of autoimmune components in peripheral blood.

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“…2). In CNS injury, the upregulation and activation of MMPs, a known component of the P2Y 2 R signaling pathway [38], can be either beneficial or detrimental depending on the length of time after the injury, the profile of the inflammatory cells at the injury site, and the substrates present [201]. During neuroinflammation, astrocytes undergo morphological and functional changes (i.e., reactive gliosis) characterized by hypertrophy, proliferation, upregulation of the intermediate filament protein glial fibrillary acidic protein, accumulation of activated glial cells around plaques, adhesion of cells to Aβ peptides, internalization and degradation of Aβ peptides by activated glial cells, expression of proteinases required for Aβ peptide catabolism, production of arachidonic acid and related proinflammatory substances in the vicinity of plaques, and regulation of regenerative processes in the brain [202][203][204][205][206].…”

Section: P2y 2 Rs In Cns Inflammationmentioning

confidence: 99%