Microcystin-LR (MC-LR) Triggers Inflammatory Responses in Macrophages

Int J Mol Sci. 2021 Sep 14;22(18):9939. doi: 10.3390/ijms22189939.

Abstract

We were the first to previously report that microcystin-LR (MC-LR) has limited effects within the colons of healthy mice but has toxic effects within colons of mice with pre-existing inflammatory bowel disease. In the current investigation, we aimed to elucidate the mechanism by which MC-LR exacerbates colitis and to identify effective therapeutic targets. Through our current investigation, we report that there is a significantly greater recruitment of macrophages into colonic tissue with pre-existing colitis in the presence of MC-LR than in the absence of MC-LR. This is seen quantitatively through IHC staining and the enumeration of F4/80-positive macrophages and through gene expression analysis for Cd68, Cd11b, and Cd163. Exposure of isolated macrophages to MC-LR was found to directly upregulate macrophage activation markers Tnf and Il1b. Through a high-throughput, unbiased kinase activity profiling strategy, MC-LR-induced phosphorylation events were compared with potential inhibitors, and doramapimod was found to effectively prevent MC-LR-induced inflammatory responses in macrophages.

Keywords: colitis; macrophages; microcystin.

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Colitis / genetics
  • Colitis / pathology
  • Colon / drug effects
  • Colon / pathology
  • Dextran Sulfate
  • Disease Models, Animal
  • Gene Expression Regulation / drug effects
  • Inflammation / genetics
  • Inflammation / pathology*
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Macrophages / pathology*
  • Male
  • Marine Toxins / toxicity*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microcystins / toxicity*
  • Naphthalenes / pharmacology
  • Protein Kinases / metabolism
  • Proteome / metabolism
  • Pyrazoles / pharmacology
  • Rats

Substances

  • Biomarkers
  • Marine Toxins
  • Microcystins
  • Naphthalenes
  • Proteome
  • Pyrazoles
  • Dextran Sulfate
  • Protein Kinases
  • cyanoginosin LR
  • doramapimod