Microglia are biosensors of neuroinflammogens and neurotoxicity, whereas astrocytes are linked only to neurotoxicity

Details

• Personal Author:
  Kelly KA ; Locker AR ; Michalovicz LT ; Miller DB ; O'Callaghan JP
• Description:
  A characteristic feature of neurotoxicity is the selective and unpredictable damage to specific neural cells. This lack of target identity constitutes a major barrier to neurotoxicity detection. Evaluating astrogliosis and microglial activation overcomes this problem as these glial cell types react to neurotoxicant exposures to reveal sites of CNS damage. Thus, astroglial and microglial biomarkers often are used as indices of neurotoxicity. Previously we showed that damage from diverse neurotoxicants initiates microglial associated neuroinflammation, the subsequent activation of STAT3 and the induction of GFAP. These findings are indicative of a link between microglial-related neuroinflammation and astrogliosis. Nevertheless, anti-inflammatory treatment with minocycline can suppress neuroinflammation instigated by neurotoxicity without suppressing astrogliosis. Given these observations, it seemed possible that indices of neuroinflammation could be dissociated from neural damage and astrogliosis, despite the fact that multiple neurotoxicity models result in STAT3 activation temporally linked to induction of GFAP. To test this possibility, we employed an acute exposure to the known inflammogen, LPS, to induce neuroinflammation. Our prior data revealed that systemic administration of LPS (2mg/kg, s.c.) did not cause neurotoxicity or astrogliosis in any brain region but did result in brainwide expression of microglia-associated proinflammatory cytokines/chemokines, Tnf-alpha, Osm, Ccl2, and Lif, as well as TSPO, a known micoroglial marker of neurotoxicity. LPS also activated STAT3 over a 12-hr post exposure period, when proinflammatory cytokine levels resolved to near baseline. Activation of STAT3 by LPS, unlike the activation associated with multiple models of neurotoxicity, was suppressible by acute pretreatment with the anti-inflammatory glucocorticoid, corticosterone. Neuroinflammation, expression of TSPO, and activation of STAT3 resulting from LPS did not affect the expression of GFAP in any brain region over a 72-hour time period. Together, these data serve to indicate that "acute phase" neuroinflammation caused by LPS can induce TSPO and activate STAT3 without resulting in neural damage or astrogliosis. The STAT3 pathway appears to serve as a dual "switch" for mediating acute neuroinflammatory responses separate from its role in mediating damage-induced astrogliosis. [Description provided by NIOSH]
• Subjects:
  Adrenal Cortex Hormones Biomarkers Immune System Nervous System Occupational Health Safety Toxicology
• Keywords:
  Biosensors Brain Electrical Activity Brain Function Brain Matter Cell Damage Cell Function Cellular Reactions Central Nervous System Corticoids Corticosteroids Cytokines Immune Reaction Neural Networks Neurological Reactions Neurological System Neurotoxicity Spinal Cord

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• ISSN:
  1096-6080
• Document Type:
  Text
• Genre:
  Abstract or Summary
• Place as Subject:
  Louisiana ; OSHA Region 3 ; OSHA Region 6 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  49
• Volume:
  150
• Issue:
  1
• NIOSHTIC Number:
  nn:20047585
• Citation:
  Toxicologist 2016 Mar; 150(1):49
• Federal Fiscal Year:
  2016
• Peer Reviewed:
  False
• Source Full Name:
  The Toxicologist. Society of Toxicology 55th Annual Meeting and ToxExpo, March 13-17, 2016, New Orleans, Louisiana
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:6a4f0649553598468ff36c61d5168fb32ab38bde1abcbfe0c418021928d1f30915621fe32a629bafe56a04933cea38b0f4721e7c016754916c5eddefee1fb30b
• Download URL:
  https://stacks.cdc.gov/view/cdc/202600/cdc_202600_DS1.pdf
• File Type:
  [PDF - 2.16 MB ]