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CD40 Receptor Knockout Protects against Microcystin-LR (MC-LR) Prolongation and Exacerbation of Dextran Sulfate Sodium (DSS)-Induced Colitis

1
Department of Medicine, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA
2
Department of Pathology, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA
3
Department of Physiology and Pharmacology, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA
4
Department of Medical Microbiology and Immunology, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA
*
Authors to whom correspondence should be addressed.
Biomedicines 2020, 8(6), 149; https://doi.org/10.3390/biomedicines8060149
Received: 14 April 2020 / Revised: 30 May 2020 / Accepted: 31 May 2020 / Published: 2 June 2020
(This article belongs to the Section Therapeutic Strategies in Different Diseases)
Inflammatory Bowel Disease (IBD) is one of the most common gastrointestinal (GI) disorders around the world, and includes diagnoses such as Crohn’s disease and ulcerative colitis. The etiology of IBD is influenced by genetic and environmental factors. One environmental perturbagen that is not well studied within the intestines is microcystin-leucine arginine (MC-LR), which is a toxin produced by cyanobacteria in freshwater environments around the world. We recently reported that MC-LR has limited effects within the intestines of healthy mice, yet interestingly has significant toxicity within the intestines of mice with pre-existing colitis induced by dextran sulfate sodium (DSS). MC-LR was found to prolong DSS-induced weight loss, prolong DSS-induced bloody stools, exacerbate DSS-induced colonic shortening, exacerbate DSS-induced colonic ulceration, and exacerbate DSS-induced inflammatory cytokine upregulation. In addition, we previously reported a significant increase in expression of the pro-inflammatory receptor CD40 in the colons of these mice, along with downstream products of CD40 activation, including plasminogen activator inhibitor-1 (PAI-1) and monocyte chemoattractant protein-1 (MCP-1). In the current study, we demonstrate that knocking out CD40 attenuates the effects of MC-LR in mice with pre-existing colitis by decreasing the severity of weight loss, allowing a full recovery in bloody stools, preventing the exacerbation of colonic shortening, preventing the exacerbation of colonic ulceration, and preventing the upregulation of the pro-inflammatory and pro-fibrotic cytokines IL-1β, MCP-1, and PAI-1. We also demonstrate the promising efficacy of a CD40 receptor blocking peptide to ameliorate the effects of MC-LR exposure in a proof-of-concept study. Our findings suggest for the first time that MC-LR acts through a CD40-dependent mechanism to exacerbate colitis. View Full-Text
Keywords: CD40; inflammatory bowel disease; dextran sulfate sodium; colitis; microcystin; colon CD40; inflammatory bowel disease; dextran sulfate sodium; colitis; microcystin; colon
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Su, R.C.; Warner, E.A.; Breidenbach, J.D.; Lad, A.; Blomquist, T.M.; Kleinhenz, A.L.; Modyanov, N.; Malhotra, D.; Kennedy, D.J.; Haller, S.T. CD40 Receptor Knockout Protects against Microcystin-LR (MC-LR) Prolongation and Exacerbation of Dextran Sulfate Sodium (DSS)-Induced Colitis. Biomedicines 2020, 8, 149.

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