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

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.

Microcystin-LR-Induced Interaction between M2 Tumor-Associated Macrophage and Colorectal Cancer Cell Promotes Colorectal Cancer Cell Migration through Regulating the Expression of TGF-β1 and CST3

“…Other studies have shown that MC-LR induces the production of inflammatory cytokines and chemokines such as IL-6, MCP-1, and CXCL10, and activates innate immune responses in mouse testicular cells, leading to testicular inflammation [ 31 ]. MC-LR has also been shown to enhance TNF-α and IL-1β expression in mouse peritoneal macrophages, thus promoting M1 polarization [ 32 ]. Similarly, our study has shown that MC-LR enhanced the expression of TGF-β1 under the co-culture system.…”

Probiotic Protects Kidneys Exposed to Microcystin-LR

“…Twenty-four hours after the challenge, the mice were euthanized, and their kidneys were snap-frozen at -85°C and prepared for RNA extraction (Figure 1). RNA was extracted using the RNeasy Plus Mini Kit (Cat # 74136, Qiagen) as previously described (14)(15)(16). A sequencing library for Poly (A) sequencing was prepared according to Illumina's mRNA sample preparation, followed by pairedended sequencing (14)(15)(16).…”

“…RNA was extracted using the RNeasy Plus Mini Kit (Cat # 74136, Qiagen) as previously described (14)(15)(16). A sequencing library for Poly (A) sequencing was prepared according to Illumina's mRNA sample preparation, followed by pairedended sequencing (14)(15)(16). According to FastQC generated quality control information, low-quality, unknown, and contaminated bases/reads were removed.…”

As We Drink and Breathe: Adverse Health Effects of Microcystins and Other Harmful Algal Bloom Toxins in the Liver, Gut, Lungs and Beyond

“…Exposure to MC-LR also resulted in greater increases in pro-inflammatory transcripts within colonic tissue (TNF-α, IL-1β, CD40, MCP-1) and the pro-fibrotic marker, PAI-1, as compared to DSS-only ingestion [ 57 ]. Mice with pre-existing colitis that were exposed to the toxin showed significantly higher macrophage infiltration in the colonic tissues as compared to the non-exposed mice [ 83 ]. Interestingly, the pro-inflammatory mediator CD40 was significantly upregulated on exposure to MC-LR, a molecular feature shared with IBD progression [ 84 ].…”