Journal
ARCHIVES OF TOXICOLOGY
Volume 93, Issue 11, Pages 3305-3320Publisher
SPRINGER HEIDELBERG
DOI: 10.1007/s00204-019-02572-w
Keywords
Aflatoxin B1; Cyclooxygenase-2; NLRP3 inflammasome; Protein phosphatase 2A; Kupffer cells; Liver inflammatory injury
Categories
Funding
- National Natural Science Foundation of China [81773465, 81973082, 81573181, 81874272]
- National Key Basic Research Program of China [2014CB560710]
- Natural Science Foundation of Fujian Province of China [2014J01372, 2015J01344]
- Scientific Research Foundation of State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics [2017ZY003]
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Aflatoxin B1 (AFB1), a food contaminant derived from Aspergillus fungi, has been reported to cause hepatic immunotoxicity via inflammatory infiltration and cytokines release. As a pro-inflammatory factor, cyclooxygenase-2 (COX-2) is widely involved in liver inflammation induced by xenobiotics. However, the mechanism by which AFB1-induced COX-2 regulates liver inflammatory injury via hepatocytes-Kupffer cells (KCs) crosstalk remains unclear and requires further elucidation. Here, we established a COX-2 upregulated model with AFB1 treatment in vivo (C57BL/6 mice, 1 mg/kg body weight, i.g, 4 weeks) and in vitro (human liver HepaRG cells, 1 mu M for 24 h). In vivo, AFB1-treated mice exhibited NLRP3 inflammasome activation, inflammatory infiltration, and increased recruitment of KCs. In vitro, dephosphorylated COX-2 by protein phosphatase 2A (PP2A)-B55 delta promoted NLRP3 inflammasome activation, including mitochondrial translocation of NLRP3, caspase 1 cleavage, and IL-1 beta release. Moreover, phosphorylated COX-2 at serine 601 (p-COX-2(Ser601)) underwent endoplasmic reticulum (ER) retention for proteasome degradation. Furthermore, pyroptosis and inflammatory response induced by AFB1 were relieved with COX-2 genetic (siPTGS2) intervention or pharmaceutic (celecoxib, 30 mg/kg body weight, i.g, 4 weeks) inhibition of COX-2 via NLRP3 inflammasome suppression in vivo and in vitro. Ex vivo, in a co-culture system with murine primary hepatocytes and KCs, activated KCs induced by damaged signals from pyroptotic hepatocytes, formed a feedback loop to amplify NLRP3-dependent pyroptosis of hepatocytes via pro-inflammatory signaling, leading to liver inflammatory injury. Taken together, our data suggest a novel mechanism that protein quality control of COX-2 determines the intracellular distribution and activation of NLRP3 inflammasome, which promotes liver inflammatory injury via hepatocytes-KCs crosstalk.
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