Blocking Notch signal in myeloid cells alleviates hepatic ischemia reperfusion injury by repressing the activation of NF-κB through CYLD.
Ischemia-reperfusion (I/R) is a major reason of hepatocyte injury during liver surgery and transplantation. Myeloid cells including macrophages and neutrophils play important roles in sustained tissue inflammation and damage, but the mechanisms regulating myeloid cells activity have been elusive. In this study, we investigate the role of Notch signaling in myeloid cells during hepatic I/R injury by using a mouse model of myeloid specific conditional knockout of RBP-J. Myeloid-specific RBP-J deletion alleviated hepatic I/R injury. RBP-J deletion in myeloid cells decreased hepatocytes apoptosis after hepatic I/R injury. Furthermore, myeloid-specific RBP-J deletion led to attenuated inflammation response in liver after I/R injury. Consistently, Notch blockade reduced the production of inflammatory cytokines by macrophages in vitro. We also found that blocking Notch signaling reduced NF-κB activation and increased cylindromatosis (CYLD) expression and knockdown of CYLD rescued reduction of inflammatory cytokines induced by Notch blockade in macrophages during I/R injury in vitro. On the other hand, activation of Notch signaling in macrophages led to increased inflammatory cytokine production and NF-κB activation and decreased CYLD expression in vitro. These data suggest that activation of Notch signaling in myeloid cells aggravates I/R injury, by enhancing the inflammation response by NF-κB through down regulation of CYLD.
Department of Hepatic Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi'an, China.
Heng-Chao
HC
Yu
Department of Clinical Laboratory, Xi-Jing Hospital, Fourth Military Medical University, Xi'an, China.
Lu
L
Bai
Department of Hepatic Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi'an, China.
Zhao-Xu
ZX
Yang
Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an 710032, China.
Hong-Yan
HY
Qin
Department of Hepatic Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi'an, China.
Kai-Shan
KS
Tao
Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an 710032, China.
Hua
H
Han
Department of Hepatic Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi'an, China.
Ke-Feng
KF
Dou
J Clin Invest. 2012 Mar;122(3):787-95
22378047
Cytokine Growth Factor Rev. 2012 Jun;23(3):69-84
22609105
Hepatology. 2013 Jul;58(1):351-62
23408710
Blood. 2007 Dec 1;110(12):4077-85
17690256
J Immunol. 2011 Nov 1;187(9):4818-25
21949019
Nat Immunol. 2004 Apr;5(4):410-7
15034575
Crit Rev Oncol Hematol. 2012 Jun;82(3):296-309
21798756
J Exp Med. 2015 Jan 12;212(1):5-14
25559892
Am J Physiol Renal Physiol. 2013 Apr 1;304(7):F948-57
23408164
Science. 1999 Apr 30;284(5415):770-6
10221902
J Hepatol. 2004 Dec;41(6):957-65
15582129
Hepatology. 2013 Jul;58(1):374-87
23460269
Cell. 2009 Apr 17;137(2):216-33
19379690
J Immunol. 2014 May 1;192(9):4342-51
24696236
Kidney Int. 2012 Oct;82(8):928-33
22673886
Development. 1997 Oct;124(20):4133-41
9374409
Hepatology. 1993 May;17(5):915-23
8387952
J Gastroenterol Hepatol. 2013 Mar;28(3):394-400
23216461
J Hepatol. 2013 Nov;59(5):1094-106
23811302
J Clin Invest. 2010 Jan;120(1):331-42
20038794
Hepatology. 2015 Jan;61(1):303-14
25145286
Hepatology. 2014 May;59(5):2034-42
24115204
Int Immunol. 2002 Jun;14(6):637-45
12039915
Hepatology. 2011 Sep 2;54(3):979-88
21633967
Nat Med. 1998 Jun;4(6):698-704
9623979
Am J Physiol Gastrointest Liver Physiol. 2006 Jun;290(6):G1083-8
16687579
Hepatology. 2013 Jan;57(1):351-61
22911673
Nat Rev Gastroenterol Hepatol. 2013 Feb;10(2):79-89
23229329
J Invest Surg. 2011;24(4):178-88
21675854
J Hepatol. 2013 Sep;59(3):583-94
23567086
Cancer Res. 2010 Jun 15;70(12):4840-9
20501839
J Gastroenterol Hepatol. 2011 Jan;26 Suppl 1:180-7
21199530
J Hepatol. 2014 Feb;60(2):306-12
24128416
Surg Clin North Am. 2010 Aug;90(4):665-77
20637940