Protectin D1 reduces concanavalin A-induced liver injury by inhibiting NF-κB-mediated CX3CL1/CX3CR1 axis and NLR family, pyrin domain containing 3 inflammasome activation

Abstract

Protectin D1 (PD1) is a bioactive product generated from docosahexaenoic acid, which may exert anti-inflammatory effects in various inflammatory diseases. However, the underlying molecular mechanism of its anti-inflammatory activity on concanavalin A (Con A)-induced hepatitis remains unknown. The aim of the present study was to investigate the protective effects of PD1 against Con A-induced liver injury and the underlying mechanisms via intravenous injection of PD1 prior to Con A administration. C57BL/6 mice were randomly divided into four experimental groups as follows: Control group, Con A group (30 mg/kg), 20 μg/kg PD1 + Con A (30 mg/kg) group and 10 μg/kg PD1 + Con A (30 mg/kg) group. PD1 pretreatment was demonstrated to significantly inhibit elevated plasma aminotransferase levels, high mobility group box 1 and liver necrosis, which were observed in Con A-induced hepatitis. Furthermore, compared with the Con A group, PD1 pretreatment prevented the production of pro-inflammatory cytokines, including tumor necrosis factor-α, interferon-γ and interleukin-2,-1β and-6. In addition, pretreatment with PD1 markedly downregulated cluster of differentiation (CD)4+, CD8+ and natural killer T (NKT) cell infiltration in the liver. PD1 pretreatment was observed to suppress the messenger RNA and protein expression levels of NLR family, pyrin domain containing 3 and Toll-like receptor (TLR) 4 in liver tissue samples. Further data indicated that PD1 pretreatment inhibited the activation of the nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) signaling pathway and chemokine (C-X3-C motif) ligand 1 (CX3CL1)/chemokine (C-X3-C motif) receptor 1 (CX3CR1) axis by preventing phosphorylation of nuclear factor of κ light polypeptide gene enhancer in B-cells inhibitor, α and NF-κB in Con A-induced liver injury. Therefore, these results suggest that PD1 administration protects mice against Con A-induced liver injury via inhibition of various inflammatory cytokines and, in part, by suppressing CD4+, CD8+ and NKT cell infiltration in the liver and the NF-κB-activated CX3CL1/CX3CR1 signaling pathway. The beneficial effect of PD1 may be associated with the inhibition of TLR4 expression and the downregulation of NF-κB activation. In conclusion, PD1 appears to be a potential natural bioproduct, and provide a promising strategy, for the prevention of hepatic injury in patients with chronic or acute liver disease.