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

  • Cell Commun Signal. 2020 May 4;18(1):70. doi: 10.1186/s12964-020-0523-3.
Li-Xing Tian  1 ,  Xin Tang  1 ,  Jun-Yu Zhu  1 ,  Li Luo  1 ,  Xiao-Yuan Ma  1 ,  Shao-Wen Cheng  2 ,  Wei Zhang  3 ,  Wan-Qi Tang  1 ,  Wei Ma  1 ,  Xue Yang  1 ,  Chuan-Zhu Lv  2 ,  Hua-Ping Liang  4
Affiliations
  • 1. State Key Laboratory of Trauma, Burns and Combined Injury, Department of Wound Infection and Drug, Daping Hospital, Army Medical University, Yuzhong District, Chongqing, China.
  • 2. Trauma Center, The First Affiliated Hospital of Hainan Medical University, Haikou, China.
  • 3. Emergency and Trauma College of Hainan Medical University, Haikou, China.
  • 4. State Key Laboratory of Trauma, Burns and Combined Injury, Department of Wound Infection and Drug, Daping Hospital, Army Medical University, Yuzhong District, Chongqing, China. [email protected].
PMID: 32366266 DOI: 10.1186/s12964-020-0523-3
Abstract

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.

Keywords
Cytochrome P450 1A1; Inflammation; Macrophages; Phagocytosis; Sepsis.
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