New Insights into the Role Microglia Play in the Etiology of Gulf War Illness

Details

• Personal Author:
  Kelly KA ; Michalovicz LT ; Miller DB ; Miller JV ; O'Callaghan JP
• Description:
  Gulf War Illness (GWI) is a multi-symptom disorder with symptoms: persistent headaches, chronic fatigue, memory loss/confusion, skin and GI problems. These features are characteristic of persistent sickness behavior, known to result from underlying microglial neuroinflammation. Chronic exposure to corticosterone (CORT), at levels associated with high physiological stress, can prime the CNS to mount an exacerbated neuroinflammatory response (increase in proinflammatory cytokines/chemokines) following systemic exposure to neurotoxicants/inflammagens. When we administered CORT (200 mg/L 0.6% EtOH in drinking water) for 7 days prior to exposure to sarin surrogate, diisopropyl fluorophosphate (DFP; 4 mg/kg, i.p.), a heightened neuroinflammatory response was observed without astrogliosis or neurodegeneration 6-72 hours after DFP exposure. While these observations recapitulated the underlying early symptoms of GWI, they did not address the persistent episodic bouts of sickness behavior that characterize the long-term nature of GWI. As the phenotype is punctuated by symptom flare-ups, systemic exposure to lipopolysaccharide (LPS - a bacterial mimic; 0.5 mg/kg, s.c.) was used to challenge the GWI phenotype 2d following DFP treatment. CORT pretreatment primes the neuroinflammatory response to produce augmented LPS-induced inflammation and a single dose of DFP significantly exacerbated this effect. Here pretreatment with CSFR1 inhibitor Pexidartinib (PLX) (290 mg/kg chow ad libitum over 28d), a compound that has been demonstrated to "eliminate" or reduce microglia in brain, was used to investigate the role microglia play in the pathogenesis of this neuroinflammatory disorder. The well documented reduction in DFP-induced mortality by CORT pretreatment was further reduced by PLX in CORT DFP (7%-36%) groups and eliminated in the DFP alone group (0%-71%). CORT pretreatment caused significant thymic involution in both control (35%) and PLX (47%) groups with PLX groups showing reduced thymic weights (11% and 27%, respectively). Brain cytokine/chemokine levels measured by qPCR revealed large increases in IL6 & OSM in response to LPS in PLX pretreated groups (LPS: 129% & 107%; CORT LPS: 178% & 181%; CORT DFP LPS: 184% & 194%, respectively) revealing a potentially proinflammatory effect of PLX. Findings potentially point to not only a non-microglial origin of these cytokines in this model, but also a protective role of microglia in certain neuroinflammatory conditions. [Description provided by NIOSH]
• Subjects:
  Behavior Blood Environmental Exposure Genetics Hazardous Substances Immune System Lipids Macrophages Nervous System Occupational Exposure Occupational Health Phosphoric Acids Safety Toxicology

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• Keywords:
  Behavior Patterns Brain Function Brain Matter Cell Function Cellular Effects Cellular Reactions Central Nervous System Chronic Exposure Corticosteroids Cytokines Dose Response Etiology Exposure Assessment Exposure Levels Genes Immune Reaction Lipopolysaccharide Military Personnel Neurological Reactions Neurotoxic Agents Neurotoxins Pathogenesis Phosphates Physiological Stress Proteins Sarin Toxic Effects Toxic Materials

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• ISSN:
  1096-6080
• Document Type:
  Text
• Genre:
  Abstract or Summary
• Place as Subject:
  OSHA Region 3 ; OSHA Region 6 ; Texas ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  162
• Issue:
  1
• NIOSHTIC Number:
  nn:20051277
• Citation:
  Toxicologist 2018 Mar; 162(1):491
• CAS Registry Number:
  Diisopropyl fluorophosphate (CAS RN 55-91-4) ; PLX 3397 (CAS RN 1029044-16-3) ; Sarin (CAS RN 107-44-8)
• Federal Fiscal Year:
  2018
• NORA Priority Area:
  Agriculture, Forestry and Fishing ; Manufacturing
• Peer Reviewed:
  False
• Source Full Name:
  The Toxicologist. Society of Toxicology 57th Annual Meeting and ToxExpo, March 11-15, 2018, San Antonio, Texas
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:a291aabb59b4c2d0870b9b8f88dac241c380bd4f7dd588718a0aa8267915aed1cb46538438264702dfd5bff2f0ec03e51a91c6e09161eb95cd1a68a3f2fbed64
• Download URL:
  https://stacks.cdc.gov/view/cdc/211325/cdc_211325_DS1.pdf
• File Type:
  [PDF - 839.47 KB ]