Corticosterone priming of the neuroinflammatory response to AChE inhibitors results in overexpression of Tlr2 and downstream targets, but not activation of the Nlrp3 inflammasome

Details

• Personal Author:
  Kelly KA ; Locker AR ; Michalovicz LT ; Miller DB ; O'Callaghan JP
• Description:
  Previously, we have shown that exposure to acetylcholinesterase inhibitors (AChEIs) produces inflammation in the mouse brain. Furthermore, this inflammation is greatly exacerbated, or "primed", by prior, chronic exposure to corticosterone (CORT). Inflammatory priming is a phenomenon commonly associated with the inflammasome, a component of the innate immune system comprised of a multitude of proteins including pattern recognition receptors, cytokines, caspases and other adaptor proteins. Prior work evaluating the response to chronic CORT exposure in rats found evidence for activation of the NLRP3 inflammasome. In this experiment, we investigated the involvement of the NLRP3 inflammasome in the neuroinflammatory response to the irreversible AChEIs, diisopropyl fluorophosphate (DFP) and chlorpyrifos (CPF), and the reversible AChEI, pyridostigmine bromide (PB), in male C57BL/6 mice with and without chronic (4 days) exposure to CORT (200 mg/L) in the drinking water prior to AChEI treatment. Here, we found the gene expression of toll-like receptor 2 (TLR2) and its downstream transcriptional targets, S100A8 and S100A9, to be increased in response to CORT DFP and CORT CPO 6 hrs after exposure, while TLR4 and NLRP3 expression were unaffected. However, NLRP3 expression was increased when CORT exposure was extended to 7 days of treatment. Past studies in our lab revealed that PB alone or with CORT pretreatment do not produce neuroinflammation, thus it is not surprising that we found no effect on any of these genes of interest following exposure to PB. Interestingly, expression of serum amyloid a (SAA1), an endogenous ligand of TLR2, was not increased by DFP or CPF, with or without prior CORT exposure. Our data indicate potential involvement of TLR2 signaling in the CORT-priming of the neuroinflammatory response to the AChEIs, DFP and CPF. However, the enhanced expression of inflammatory cytokines in the brain following exposure to CORT and these AChEIs is independent of NLRP3 expression, which appears to be a primary effect of prolonged CORT exposure. By further examining the role of TLR2 in an augmented neuroinflammatory response following the combined CORT and AChEI exposure, we can identify potential targets for the treatment of illness associated with these exposures, such as Gulf War Illness. [Description provided by NIOSH]
• Subjects:
  Adrenal Cortex Hormones Animals Biomarkers Bromides Immune System Laboratories Nervous System Occupational Health Phosphoric Acids Safety Toxicology

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• Keywords:
  Acetylcholinesterase Brain Function Brain Matter Cell Damage Cell Function Cellular Reactions Chlorpyrifos Cholinesterase Inhibitors Chronic Inflammation Corticoids Corticosteroids Cytokines Immune Reaction Immune System Laboratory Animals Military Personnel Neurological Reactions Neurological System Neurotoxicity Phosphates Proteins

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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:
  49-50
• Volume:
  150
• Issue:
  1
• NIOSHTIC Number:
  nn:20047587
• Citation:
  Toxicologist 2016 Mar; 150(1):49-50
• CAS Registry Number:
  Chlorpyrifos (CAS RN 2921-88-2) ; Diisopropyl fluorophosphate (CAS RN 55-91-4) ; Pyridostigmine bromide (CAS RN 101-26-8)
• 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-512:7c6ffc7233f4056f53c6d335251f5519dc754838ac59c34374eddde864cd7ab451829987290acd99899687749272c0a40a9ab093e0ad5e67e9fa8c4acfd8e7ad
• Download URL:
  https://stacks.cdc.gov/view/cdc/202602/cdc_202602_DS1.pdf
• File Type:
  [PDF - 451.82 KB ]