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

• Published in: The FASEB journal Vol. 34; no. 6; p. 7718
• Main Authors: Liu, Gang, Baird, Alan W, Parsons, Marie J, Fan, Kening, Skerrett-Byrne, David A, Nair, Prema M, Makanyengo, Samwel, Chen, Jinbiao, Neal, Rachel, Goggins, Bridie J, Tay, Hock, Mathe, Andrea, Soh, Wai S, Minahan, Kyra, Hansbro, Phil M, Nixon, Brett, McCaughan, Geoffrey W, Holtmann, Gerald, Colgan, Sean P, Keely, Simon
• Format: Journal Article
• Language: English
• Published: United States 01.06.2020
• Subjects: Animals; Caspase 1 - metabolism; Cells, Cultured; Colitis - chemically induced; Colitis - metabolism; Colitis - pathology; Colon - metabolism; Colon - pathology; Dextran Sulfate - pharmacology; Hepatocytes - drug effects; Hepatocytes - metabolism; Hepatocytes - pathology; Humans; Inflammasomes - metabolism; Inflammation - chemically induced; Inflammation - metabolism; Inflammation - pathology; Inflammatory Bowel Diseases - metabolism; Inflammatory Bowel Diseases - pathology; Interleukin-1beta - metabolism; Kupffer Cells - metabolism; Kupffer Cells - pathology; Liver - drug effects; Liver - metabolism; Liver - pathology; Male; Mice; Mice, Inbred C57BL; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Platelet Membrane Glycoproteins - metabolism; Receptors, G-Protein-Coupled - metabolism; Toll-Like Receptor 4 - metabolism; PAFR; extraintestinal manifestations in liver; inflammatory bowel disease
• ISSN: 1530-6860
• DOI: 10.1096/fj.201901779R

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.