Organic Dust-Induced Mitochondrial Dysfunction Could Be Targeted via cGAS-STING or Cytoplasmic NOX-2 Inhibition Using Microglial Cells and Brain Slice Culture Models

Details

• Personal Author:
  Bhat SM ; Charavaryamath C ; Charli A ; Kanthasamy AG ; Karriker LA ; Kondru N ; Massey N ; Shrestha D
• Description:
  Organic dust (OD) exposure in animal production industries poses serious respiratory and other health risks. OD consisting of microbial products and particulate matter and OD exposure-induced respiratory inflammation are under investigation. However, the effect of OD exposure on brain remains elusive. We show that OD exposure of microglial cells induces an inflammatory phenotype with the release of mitochondrial DNA (mt-DNA). Therefore, we tested a hypothesis that OD exposure-induced secreted mt-DNA signaling drives the inflammation. A mouse microglial cell line was treated with medium or organic dust extract (ODE, 1% v/v) along with either phosphate-buffered saline (PBS) or mitoapocynin (MA, 10 µmol). Microglia treated with control or anti-STING siRNA were exposed to medium or ODE. Mouse organotypic brain slice cultures (BSCs) were exposed to medium or ODE with or without MA. Various samples were processed to quantify mitochondrial reactive oxygen species (mt-ROS), mt-DNA, cytochrome c, TFAM, mitochondrial stress markers and mt-DNA-induced signaling via cGAS-STING and TLR9. Data were analyzed and a p value of ≤ 0.05 was considered significant. MA treatment decreased the ODE-induced mt-DNA release into the cytosol. ODE increased MFN1/2 and PINK1 but not DRP1 and MA treatment decreased the MFN2 expression. MA treatment decreased the ODE exposure-induced mt-DNA signaling via cGAS-STING and TLR9. Anti-STING siRNA decreased the ODE-induced increase in IRF3, IFN-beta and IBA-1 expression. In BSCs, MA treatment decreased the ODE-induced TNF-alpha, IL-6 and MFN1. Therefore, OD exposure-induced mt-DNA signaling was curtailed through cytoplasmic NOX-2 inhibition or STING suppression to reduce brain microglial inflammatory response. [Description provided by NIOSH]
• Subjects:
  Dust Immune System Laboratories Occupational Health Safety
• Keywords:
  Author Keywords: Inflammation Brain Function Brain Matter Cell Function Cell Signaling Cellular Effects CGAS-STING Immune Reaction Laboratory Animals Microglia Mitochondrial DNA Organic Dust Organic Dusts Proteins Reactive Oxygen Species ROS

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• ISSN:
  0302-766X
• Document Type:
  Text
• Funding:
  Cooperative Agreement
• Genre:
  Journal Article
• Place as Subject:
  Florida ; Iowa ; OSHA Region 3 ; OSHA Region 4 ; OSHA Region 7 ; Pennsylvania
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  465-486
• Volume:
  384
• Issue:
  2
• NIOSHTIC Number:
  nn:20062215
• Citation:
  Cell Tissue Res 2021 May; 384(2):465-486
• Contact Point Address:
  Chandrashekhar Charavaryamath, Department of Biomedical Sciences, Veterinary Medicine Building, Iowa State University, Ames, IA 50011, USA
• Email:
  chandru@iastate.edu
• Federal Fiscal Year:
  2021
• NORA Priority Area:
  Agriculture, Forestry and Fishing
• Performing Organization:
  University of Iowa, Iowa City
• Peer Reviewed:
  True
• Start Date:
  20010930
• Source Full Name:
  Cell and Tissue Research
• End Date:
  20270929
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:bf11df68dc3dda6aa3a9f6ee164b5eb13223be00465dd1263adf6201ff51db15fc816c641e29128a243b34a1a82b6627bb621fb6527794d79e69051323b99e96
• Download URL:
  https://stacks.cdc.gov/view/cdc/225510/cdc_225510_DS1.pdf
• File Type:
  [PDF - 1.21 MB ]