Neuroinflammation and Gulf War Illness: The Role of Microglia in the Response to In-Theater Toxicant Exposure

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 similarities to the features of sickness behavior. Previously, we have demonstrated that, like sickness behavior, GWI is associated with underlying neuroinflammation. In particular, toxic exposures experienced by soldiers during the Gulf War such as pesticides and nerve agents, as well as physiological stress, have led to a chronic, primed neuroinflammatory state that results in an exacerbated response to subsequent inflammatory challenges. The significant elaboration of inflammatory cytokines related to the neuroinflammatory priming observed in our GWI mouse model indicates that this illness may be the result of long-term alterations in the brain's resident immune cells, namely microglia. Here, we have investigated the potential role of microglia in GWI using the CX3CR1 -/- mouse strain and minocycline, an anti-inflammatory drug with effects on microglia. Adult male C57BL/6J or CX3CR1 -/- mice were exposed to our GWI model consisting of corticosterone (CORT) in the drinking water at levels associated with high physiological stress for 7 days followed by exposure to the nerve agent surrogate, diisopropyl fluorophosphate (DFP), on day 8 and a subsequent immune challenge with lipopolysaccharide (LPS) on day 10. C57BL/6J mice that were given minocycline received a single dose 30 minutes prior to LPS. To test whether minocycline or CX3CR1 -/- disrupted LPS-induced inflammation, an additional cohort of animals were exposed to LPS exposure on day 8 in place of DFP. Interestingly, neither CX3CR1 -/- nor minocycline-treated mice exhibited major differences in cytokine mRNA expression following CORT+LPS exposure compared to controls. However, both CX3CR1 -/- and minocycline treatment removed the contribution of DFP to the GWI phenotype, reducing cytokine mRNA expression to levels comparable to CORT+LPS treatment. The recovery of the GWI phenotype to CORT+LPS levels is clinically significant, because this condition mimics a "healthy sick" state in which stress may potentiate inflammatory conditions. These results suggest that microglia play a crucial role in the development/maintenance of GWI particularly in response to DFP and that drugs with modulatory effects on microglia show promise for the treatment of veterans suffering with GWI. [Description provided by NIOSH]
• Subjects:
  Behavior Genetics Hazardous Substances Immune System Insecticides Laboratories Lipids Nervous System Occupational Exposure Occupational Health Phosphoric Acids Safety Toxicology

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• Keywords:
  Analytical Models Behavior Patterns Brain Function Brain Matter Cell Alteration Cell Function Cellular Effects Cellular Reactions Chronic Exposure Chronic Inflammation Corticosteroids Cytokines Dose Response Drugs Exposure Assessment Gene Expression Genes Immune Reaction Immune System Immunotoxins Laboratory Animals Laboratory Testing Lipopolysaccharide Military Personnel Neurotoxic Agents Neurotoxins Pesticides Phosphates Physiological Stress Proteins Ribonucleic Acids RNA 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:20051279
• Citation:
  Toxicologist 2018 Mar; 162(1):492
• CAS Registry Number:
  Diisopropyl fluorophosphate (CAS RN 55-91-4) ; Minocycline (CAS RN 10118-90-8)
• Federal Fiscal Year:
  2018
• 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:c9cedac1b423bb7e07740d1eb1977945441c12161f09a8c66b0389bc8066756b904476e8e4b62213086e865f2b0568e948c924dd80671dba3e421adc62c1e0dc
• Download URL:
  https://stacks.cdc.gov/view/cdc/211326/cdc_211326_DS1.pdf
• File Type:
  [PDF - 832.82 KB ]