Abstract
Neutrophils play an essential role in the control of inflammatory diseases. However, whether cannabinoid receptors (CBs) play a role in neutrophil chemotaxis and NETosis in sterile liver inflammation remains unknown. The expression of marker genes on neutrophils was characterized by FACS, immunofluorescence, qRT-PCR, and Western blot. The amount of neutrophils was significantly elevated from 7 days and reached the peak at 2 weeks in carbon tetrachloride (CCl4)-treated mouse liver. The mRNA expression of neutrophil marker Ly6G had positive correlation with CB1 and CB2 expression in injured liver. In vitro CBs were abundantly expressed in isolated neutrophils and CB1 agonist ACEA promoted the chemotaxis and cytoskeletal remodeling, which can be suppressed by CB1 antagonist AM281. Moreover, ACEA induced NETosis, myeloperoxidase release from lysosome and ROS burst, indicating neutrophil activation, via Gαi/o. Conversely, CB2 agonist JWH133 had no effect on neutrophil function. ROS and p38 MAPK signaling pathways were involved in CB1-mediated neutrophil function, and ROS was upstream of p38 MAPK. CB1 blockade in vivo significantly attenuated neutrophil infiltration and liver inflammation in CCl4-treated mice. Taken together, CB1 mediates neutrophil chemotaxis and NETosis via Gαi/o/ROS/p38 MAPK signaling pathway in liver inflammation, which represents an effective therapeutic strategy for liver diseases.
Highlights
Neutrophils are the most abundant white blood cells and among the first cells recruited to an inflammatory site, mediating the early responses to tissue injury [1]
Our findings suggest that CB1 but not CB2 mediates neutrophil chemotaxis and NETosis in vitro, which are dependent of ROS and MAPK signaling pathways
Since ROS burst was markedly induced by ACEA, we explored whether ROS was involved in CB1-mediated neutrophil chemotaxis and NETosis
Summary
Neutrophils are the most abundant white blood cells and among the first cells recruited to an inflammatory site, mediating the early responses to tissue injury [1]. In liver ischemia/reperfusion, interleukin-33, which is released from liver sinusoidal endothelial cells, promotes NETosis of infiltrating neutrophils and exacerbates inflammatory injury [15]. Disruption of the miR-223 gene exacerbates acetaminophen-induced hepatic neutrophil infiltration, oxidative stress, and injury, and enhances TLR9 ligand-mediated activation of pro-inflammatory mediators in neutrophils [16]. It remains unknown about the mediator and underlying molecular mechanism of regulating neutrophil recruitment and activation during chronic liver injury. Our previous studies have found that CB1 promotes the infiltration and activation of bone marrow (BM)-derived monocytes/macrophages in carbon tetrachloride (CCl4 )-induced liver injury mouse model, which could be inhibited by the blockade of CB1 [26,27]. Blockade of CB1 in vivo reduces the infiltration and activation of neutrophils and attenuates liver injury in CCl4 -treated mice, which may represent an effective therapeutic strategy for liver diseases
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