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Editors Selection IGR 8-3

Basic research: Microglia and astrocytes

Jonathan Kipnis

Comment by Jonathan Kipnis on:

14058 Interleukin-6 protects retinal ganglion cells from pressure-induced death, Sappington RM; Chan M; Calkins DJ, Investigative Ophthalmology and Visual Science, 2006; 47: 2932-2942


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The work by Sappington et al. (885), addresses the role played by glial cells (microglia and astrocytes) in the progression of glaucoma. Authors are guided by a widely accepted theory that glial cells in the optic nerve head influence the survival of retinal ganglion cells (RGCs) in glaucoma. To address the relevance of glial cells in glaucoma, authors established primary cultures of retinal cells - RGCs, astrocytes and microglia. Although the most established method for RGC isolation is panning, established by Barres and colleagues,1 this current method of magnetic separation seams to be efficient and leads to a high purity (98%) of specific cells.

To mimic glaucomatous conditions in vitro, RGCs were exposed to hydrostatic pressure of 70 mmHg. This pressure is significantly higher than that in glaucomatous patients, normally ranging between 20 to 35 mmHg, and this is one of the weaknesses of this work. Elevated pressure increased apoptotic (TUNEL positive) RGCs and induced Bax, and Bcl-2 expression. The response of glial cells to elevated pressure was measured in terms of IL-6 production, which was decreased in astrocytes, whereas significantly increased in microglia exposed to high pressure. Apoptosis/necrosis induced by high pressure in astrocytes/microglia has not been examined, which is another weakness of this work. As such, the possibility that astroglial cells are more susceptible to pressure and, therefore, the reduced concentration of IL-6 in the media is due to astroglial cell death has not been addressed.

The IL-6 production was decreased in astrocytes as a response of glial cells to elevated pressure; whereas significantly increased in microglia exposed to high pressure
The conditioned media obtained from astrocytes exposed to high pressure (ACM), exacerbated RGC pressure-induced death, whereas conditioned media from microglial cells (MCM) was neuroprotective. Substitution of the conditioned media by recombinant IL-6 induced significant neuroprotection of RGCs exposed to pressure. While the experiments are well designed to address the hypothesis and the conclusions are supported by the data and are obviously not affected by any financial, intellectual, or other conflict of interest, some questions remain unanswered. Thus for example, if depletion of IL-6 from ACM makes it toxic to neurons under ambient pressure, why it does not further exacerbate pressure-induced RGC death? The results were obtained with only 10% of conditioned media in the RGC; therefore, could the effects be more prominent if higher concentrations of ACM/MSM were applied? Would MCM counteract the toxic effect of ACM (or vice versa)? Would high dose of IL-6 (120 pg/ml) overcome the neurotoxic effect induced by ACM? Would IL-6 and/or MCM protect RGC death induced by factors, other than high pressure (e.g., glutamate intoxication)? What are the factors present in ACM that induce neuronal death? Identification and subsequent neutralization of these factors in combination with recombinant IL-6 may be the therapy of choice for high-pressure glaucoma.

Opposing reports on the role of IL-6 in neuronal survival have been suggested by different groups.2-7 While several works show beneficial aspects of IL-6 in CNS trauma in general, such as the role of IL-6 as a signaling mechanism that prevents neuronal cell death after ischemia:3 others suggest, for example, that IL-6-deficient mice show an increased resistance of RGC to glutamate toxicity8 or that neutralization of IL-6 signaling in the acute phase of spinal cord injury represents an attractive option for the treatment.9 As for the role of microglia under neurodegeneration, these cells are usually perceived as contributors to neurodegeneration;10-12 whereas, several recent works suggest that the modulation of microglial phenotype gives rise to neuroprotective or even neuro-regenerative cells.13-17 With regards to the astrocytes, which are agreeably perceived as supportive cells in the CNS, authors failed to demonstrate that toxic compounds found in the ACM are a result of astrocyte response to pressure, rather than intracellular toxic contents released from astrocytes due to pressure-induced necrotic death.

Overall, this study addresses the important role of glial cells in glaucoma. However, proof of concept in vivo models will be required to address therapeutic relevance of this work. Moreover, a better understanding of the mechanisms underlying IL-6 differential release by glial cells and its effect on neurons as well as its potential side effects need to be elucidated before considering a possibility of translation of this knowledge to clinical trials.

References

  1. Barres BA, Silverstein BE, Corey DP, Chun LL. Immunological, morphological, and electrophysiological variation among retinal ganglion cells purified by panning. Neuron 1988; 1: 791-803.
  2. Shioda S, Ohtaki H, Nakamachi T, et al. Pleiotropic functions of PACAP in the CNS: neuroprotection and neurodevelopment. Ann NY Acad Sci 2006; 1070: 550-560.
  3. Ohtaki H, Nakamachi T, Dohi K, et al. Pituitary adenylate cyclase-activating polypeptide (PACAP) decreases ischemic neuronal cell death in association with IL-6. Proc Natl Acad Sci USA 2006; 103: 7488-7493.
  4. Gruol DL, Nelson TE. Purkinje neuron physiology is altered by the inflammatory factor interleukin-6. Cerebellum 2005; 4: 198-205.
  5. Biber K, Lubrich B, Fiebich BL, et al. Interleukin-6 enhances expression of adenosine A(1) receptor mRNA and signaling in cultured rat cortical astrocytes and brain slices. Neuropsychopharmacology 2001; 24: 86-96.
  6. Carlson NG, Wieggel WA, Chen J, et al. Inflammatory cytokines IL-1 alpha, IL-1 beta, IL-6, and TNF-alpha impart neuroprotection to an excitotoxin through distinct pathways. J Immunol 1999; 163: 3963-3968.
  7. Rothwell NJ, Strijbos PJ. Cytokines in neurodegeneration and repair. Int J Dev Neurosci 1995; 13: 179-185.
  8. Fisher J, Mizrahi T, Schori H, et al. Increased post-traumatic survival of neurons in IL-6-knockout mice on a background of EAE susceptibility. J Neuroimmunol 2001; 119: 1-9.
  9. Okada S, Nakamura M, Mikami Y, et al. Blockade of interleukin-6 receptor suppresses reactive astrogliosis and ameliorates functional recovery in experimental spinal cord injury. J Neurosci Res 2004; 76: 265-276.
  10. Festoff BW, Ameenuddin S, Arnold PM, et al. Minocycline neuroprotects, reduces microgliosis, and inhibits caspase protease expression early after spinal cord injury. J Neurochem 2006; 97: 1314-1326.
  11. Flaris NA, Densmore TL, Molleston MC, Hickey WF. Characterization of microglia and macrophages in the central nervous system of rats: definition of the differential expression of molecules using standard and novel monoclonal antibodies in normal CNS and in four models of parenchymal reaction. Glia 1993; 7: 34-40.
  12. Sargsyan SA, Monk PN, Shaw PJ. Microglia as potential contributors to motor neuron injury in amyotrophic lateral sclerosis. Glia 2005; 51: 241-253.
  13. Shaked I, Tchoresh D, Gersner R, et al. Protective autoimmunity: interferon-gamma enables microglia to remove glutamate without evoking inflammatory mediators. J Neurochem 2005; 92: 997-1009.
  14. Schwartz M. Macrophages and microglia in central nervous system injury: are they helpful or harmful? J Cereb Blood Flow Metab 2003; 23: 385-394.
  15. Kipnis J, Avidan H, Caspi RR, Schwartz M. Dual effect of CD4+CD25+ regulatory T cells in neurodegeneration: a dialogue with microglia. Proc Natl Acad Sci USA 2004; 101 Suppl 2: 14663-14669.
  16. Butovsky O, Talpalar AE, Ben-Yaakov K, Schwartz M. Activation of microglia by aggregated beta-amyloid or lipopolysaccharide impairs MHC-II expression and renders them cytotoxic whereas IFN-gamma and IL-4 render them protective. Mol Cell Neurosci 2005; 29: 381-393.
  17. Butovsky O, Landa G, Kunis G, et al. Induction and blockage of oligodendrogenesis by differently activated microglia in an animal model of multiple sclerosis. J Clin Invest 2006; 116: 905-915.

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