PMID- 32498446
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20200928
IS  - 2227-9059 (Print)
IS  - 2227-9059 (Electronic)
IS  - 2227-9059 (Linking)
VI  - 8
IP  - 6
DP  - 2020 Jun 2
TI  - CD40 Receptor Knockout Protects against Microcystin-LR (MC-LR) Prolongation and 
      Exacerbation of Dextran Sulfate Sodium (DSS)-Induced Colitis.
LID - 10.3390/biomedicines8060149 [doi]
LID - 149
AB  - 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-1beta, 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.
FAU - Su, Robin C
AU  - Su RC
AUID- ORCID: 0000-0002-7423-0939
AD  - Department of Medicine, The University of Toledo College of Medicine and Life 
      Sciences, Toledo, OH 43614, USA.
FAU - Warner, Emily A
AU  - Warner EA
AD  - Department of Medicine, The University of Toledo College of Medicine and Life 
      Sciences, Toledo, OH 43614, USA.
FAU - Breidenbach, Joshua D
AU  - Breidenbach JD
AUID- ORCID: 0000-0002-5892-1879
AD  - Department of Medicine, The University of Toledo College of Medicine and Life 
      Sciences, Toledo, OH 43614, USA.
FAU - Lad, Apurva
AU  - Lad A
AD  - Department of Medicine, The University of Toledo College of Medicine and Life 
      Sciences, Toledo, OH 43614, USA.
FAU - Blomquist, Thomas M
AU  - Blomquist TM
AD  - Department of Pathology, The University of Toledo College of Medicine and Life 
      Sciences, Toledo, OH 43614, USA.
FAU - Kleinhenz, Andrew L
AU  - Kleinhenz AL
AD  - Department of Medicine, The University of Toledo College of Medicine and Life 
      Sciences, Toledo, OH 43614, USA.
FAU - Modyanov, Nikolai
AU  - Modyanov N
AD  - Department of Physiology and Pharmacology, The University of Toledo College of 
      Medicine and Life Sciences, Toledo, OH 43614, USA.
FAU - Malhotra, Deepak
AU  - Malhotra D
AD  - Department of Medicine, The University of Toledo College of Medicine and Life 
      Sciences, Toledo, OH 43614, USA.
FAU - Kennedy, David J
AU  - Kennedy DJ
AUID- ORCID: 0000-0001-5265-0142
AD  - Department of Medicine, The University of Toledo College of Medicine and Life 
      Sciences, Toledo, OH 43614, USA.
AD  - Department of Medical Microbiology and Immunology, The University of Toledo 
      College of Medicine and Life Sciences, Toledo, OH 43614, USA.
FAU - Haller, Steven T
AU  - Haller ST
AUID- ORCID: 0000-0002-6919-6342
AD  - Department of Medicine, The University of Toledo College of Medicine and Life 
      Sciences, Toledo, OH 43614, USA.
AD  - Department of Medical Microbiology and Immunology, The University of Toledo 
      College of Medicine and Life Sciences, Toledo, OH 43614, USA.
LA  - eng
GR  - 4241/Ohio Department of Higher Education/
PT  - Journal Article
DEP - 20200602
PL  - Switzerland
TA  - Biomedicines
JT  - Biomedicines
JID - 101691304
PMC - PMC7345682
OTO - NOTNLM
OT  - CD40
OT  - colitis
OT  - colon
OT  - dextran sulfate sodium
OT  - inflammatory bowel disease
OT  - microcystin
COIS- The authors declare no conflict of interest.
EDAT- 2020/06/06 06:00
MHDA- 2020/06/06 06:01
PMCR- 2020/06/02
CRDT- 2020/06/06 06:00
PHST- 2020/04/14 00:00 [received]
PHST- 2020/05/30 00:00 [revised]
PHST- 2020/05/31 00:00 [accepted]
PHST- 2020/06/06 06:00 [entrez]
PHST- 2020/06/06 06:00 [pubmed]
PHST- 2020/06/06 06:01 [medline]
PHST- 2020/06/02 00:00 [pmc-release]
AID - biomedicines8060149 [pii]
AID - biomedicines-08-00149 [pii]
AID - 10.3390/biomedicines8060149 [doi]
PST - epublish
SO  - Biomedicines. 2020 Jun 2;8(6):149. doi: 10.3390/biomedicines8060149.