Cytochrome P450 1A1 enhances inflammatory responses and impedes phagocytosis of bacteria in macrophages during sepsis

• Published in: Cell communication and signaling 2020-05, Vol.18 (1), p.70-70, Article 70
• Main Authors: Tian, Li-Xing, Tang, Xin, Zhu, Jun-Yu, Luo, Li, Ma, Xiao-Yuan, Cheng, Shao-Wen, Zhang, Wei, Tang, Wan-Qi, Ma, Wei, Yang, Xue, Lv, Chuan-Zhu, Liang, Hua-Ping
• Format: Article
• Language: English
• Subjects: Antibodies; Bacteria; Bacterial infections; Binding sites; CRISPR; Cytochrome P450; Cytochrome P450 1A1; Hydroxylase; Immune clearance; Inflammation; Interleukin 6; Laboratory animals; Lipopolysaccharides; Macrophages; Manufacturers; Metabolism; Monocytes; Pathogens; Peritoneum; Phagocytosis; Proteins; Scavenger receptors; Sepsis; Transcription factors; Tumor necrosis factor-α
• ISSN: 1478-811X; 1478-811X
• DOI: 10.1186/s12964-020-0523-3

The hydroxylase cytochrome P450 1A1 (CYP1A1) is regulated by the inflammation-limiting aryl hydrocarbon receptor (AhR), but CYP1A1 immune functions remain unclear. We observed CYP1A1 overexpression in peritoneal macrophages (PMs) isolated from mice following LPS or heat-killed Escherichia. coli (E. coli) challenge. CYP1A1 overexpression augmented TNF-α and IL-6 production in RAW264.7 cells (RAW) by enhancing JNK/AP-1 signalling. CYP1A1 overexpression also promoted 12S-hydroxy-5Z,8Z,10E,14Z-eicosatetraenoic acid (12(S)-HETE) production in activated RAW, while a 12(S)-HETE antibody attenuated and 12(S)-HETE alone induced inflammatory responses. Macrophages harbouring hydroxylase-deficient CYP1A1 demonstrated reduced 12(S)-HETE generation and LPS-induced TNF-α/IL-6 secretion. CYP1A1 overexpression also impaired phagocytosis of bacteria via decreasing the expression of scavenger receptor A (SR-A) in PMs. Mice injected with CYP1A1-overexpressing PMs were more susceptible to CLP- or E. coli-induced mortality and bacteria invading, while Rhapontigenin, a selective CYP1A1 inhibitor, improved survival and bacteria clearance of mice in sepsis. CYP1A1 and 12(S)-HETE were also elevated in monocytes and plasma of septic patients and positively correlated with SOFA scores. Macrophage CYP1A1 disruption could be a promising strategy for treating sepsis. Video abstract.