Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 18, Pages -Publisher
MDPI
DOI: 10.3390/ijms22189939
Keywords
microcystin; colitis; macrophages
Funding
- Harmful Algal Bloom Research Initiative grant from the Ohio Department of Higher Education
- David and Helen Boone Foundation Research Fund
- University of Toledo Women
- Philanthropy Genetic Analysis Instrumentation Center
- National Heart, Lung, And Blood Institute of the National Institutes of Health [F31HL160178]
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In patients with colitis, microcystin-LR can exacerbate inflammation by affecting macrophage activation, and doramapimod has been found to effectively prevent MC-LR-induced inflammatory responses.
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.
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