Platelet activating factor receptor acts to limit colitis-induced liver inflammation.

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2020 Jun

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Liver inflammation is a common extraintestinal manifestation in inflammatory bowel disease (IBD), yet, the mechanisms driving gut-liver axis inflammation remain poorly understood. IBD leads to a breakdown in the integrity of the intestinal barrier causing an increase in portal and systemic gut-derived antigens, which challenge the liver. Here, we examined the role of platelet activating factor receptor (PAFR) in colitis-associated liver damage using dextran sulfate sodium (DSS) and anti-CD40-induced colitis models. Both DSS and anti-CD40 models exhibited liver inflammation associated with colitis. Colitis reduced global PAFR protein expression in mouse livers causing an exclusive re-localization of PAFR to the portal triad. The global decrease in liver PAFR was associated with increased sirtuin 1 while relocalized PAFR expression was limited to Kupffer cells (KCs) and co-localized with toll-like receptor 4. DSS activated the NLRP3-inflammasome and increased interleukin (IL)-1β in the liver. Antagonism of PAFR amplified the inflammasome response by increasing NLRP3, caspase-1, and IL-1β protein levels in the liver. LPS also increased NLRP3 response in human hepatocytes, however, overexpression of PAFR restored the levels of NLPR3 and caspase-1 proteins. Interestingly, KCs depletion also increased IL-1β protein in mouse liver after DSS challenge. These data suggest a protective role for PAFR-expressing KCs during colitis and that regulation of PAFR is important for gut-liver axis homeostasis. © 2020 Federation of American Societies for Experimental Biology.

Citation

Gang Liu, Alan W Baird, Marie J Parsons, Kening Fan, David A Skerrett-Byrne, Prema M Nair, Samwel Makanyengo, Jinbiao Chen, Rachel Neal, Bridie J Goggins, Hock Tay, Andrea Mathe, Wai S Soh, Kyra Minahan, Phil M Hansbro, Brett Nixon, Geoffrey W McCaughan, Gerald Holtmann, Sean P Colgan, Simon Keely. Platelet activating factor receptor acts to limit colitis-induced liver inflammation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2020 Jun;34(6):7718-7732