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.
Highlights
Harmful algal blooms have quickly become a global health concern, appearing in freshwater environments around the world each year [1]
Hematoxylin and eosin (H&E) staining of formalin-fixed paraffinembedded (FFPE) colonic sections revealed large numbers of inflammatory cell infiltrates in Dextran sodium sulfate (DSS) mice, with increased infiltrates in DSS+MC-LR mice [9]
We have previously shown that MC-LR has limited effects within healthy colons but exacerbates the overall disease state within colons with pre-existing colitis [9]
Summary
Harmful algal blooms have quickly become a global health concern, appearing in freshwater environments around the world each year [1]. These blooms, which are an overgrowth of cyanobacteria, are capable of producing cyanotoxins such as Microcystins, of which, microcystin-LR (MC-LR) is one of the most frequently produced and one of the most toxic forms [2]. We were the first to report that MC-LR has minimal GI effects in healthy mice, but significant GI toxicity in mice with pre-existing colitis [9]. Dextran sodium sulfate (DSS) can be used in mice to model colitis.
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