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

• Alternative Title:
  Cell Tissue Res
• Personal Author:
  Massey, Nyzil ; Shrestha, Denusha ; Bhat, Sanjana Mahadev ; Kondru, Naveen ; Charli, Adhithiya ; Karriker, Locke A. ; Kanthasamy, Anumantha G. ; Charavaryamath, Chandrashekhar
• 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-β and IBA-1 expression. In BSCs, MA treatment decreased the ODE-induced TNF-α, 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.
• Subjects:
  Animals Bacterial Proteins Brain Disease Models, Animal Dust Mice Microglia Mitochondria NADH, NADPH Oxidoreductases Signal Transduction
• Keywords:
  CGAS-STING Inflammation Microglia Mitochondrial DNA Organic Dust
• Source:
  Cell Tissue Res. 384(2):465-486
• Pubmed ID:
  33687557
• Pubmed Central ID:
  PMC8154696
• Document Type:
  Journal Article
• Funding:
  R01 ES027245/ES/NIEHS NIH HHSUnited States/ ; R01 NS100090/NS/NINDS NIH HHSUnited States/ ; U54 OH007548/OH/NIOSH CDC HHSUnited States/ ; R01 ES026892/ES/NIEHS NIH HHSUnited States/ ; ES026892, ES027245 and NS100090/NH/NIH HHSUnited States/
• Volume:
  384
• Issue:
  2
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:c405270c8f3572883d232faaa47894a459a9fc22f3f0edd35af1b69e96202730
• Download URL:
  https://stacks.cdc.gov/view/cdc/106662/cdc_106662_DS1.pdf
• File Type:
  [PDF - 2.45 MB ]