Contribution and underlying mechanisms of CXCR4 overexpression in patients with systemic lupus erythematosus.
Aberrant expression of CXCR4 has been indicated to play a role in the pathogenesis of systemic lupus erythematosus (SLE), but the mechanism of CXCR4 dysregulation in SLE is unclear. This study is aimed to explore the clinical significance and possible mechanisms of abnormal CXCR4 expression on B cells from patients with untreated SLE. Expression of CXCR4 on peripheral B cells was determined by flow cytometry and western blotting. Freshly isolated B cells were cultured with exogenous interleukin 21(IL-21) in the presence or absence of CD40 ligand (CD40L) plus anti-IgM antibody (aIgM), and changes in CXCR4 expression were detected. Involvement of phosphatidylinositol 3 kinase (PI3K)/Akt and Janus kinase/Signal transducer and activator of transcription (JAK/STAT) signaling pathways was assessed by adding blocking agents Ly294002 and AG490. Since CD63 is reported to mediate endosomal recruitment of CXCR4 and BCL6 is capable of silencing CD63 gene transcription, we also measured BCL6 and CD63 gene transcription with real-time PCR. It was shown that CXCR4 expression on B cells was significantly upregulated in SLE patients, especially in those with lupus nephritis, and was positively correlated with SLE Disease Activity Index scores and negatively with the serum complement 3 levels (P<0.05). Downregulation of CXCR4 by IL-21 was intact. In contrast, a similar effect of aIgM plus CD40L in downregulating CXCR4 expression was defective in SLE patients but was restored by co-stimulation with IL-21 in vitro. Both Ly294002 and AG490 promoted downregulation of surface CXCR4 expression on B cells from SLE patients (P=0.078 and P=0.064). Furthermore, B cells from SLE patients exhibited diminished CD63 mRNA and enhanced BCL6 mRNA expression (both P<0.05). To sum up, CXCR4 was overexpressed on SLE B cells, positively correlating with disease activity and kidney involvement. Overactivation of the PI3K/Akt and JAK/STAT pathways as well as defective CD63 synthesis may contribute to CXCR4 dysregulation in SLE.
Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, Beijing 100730, China.
Li-Dan
LD
Zhao
Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, Beijing 100730, China.
Di
D
Liang
Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, Beijing 100730, China.
Xiang-Ni
XN
Wu
Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, Beijing 100730, China.
Yang
Y
Li
Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, Beijing 100730, China.
Jing-Wen
JW
Niu
Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, Beijing 100730, China.
Chen
C
Zhou
Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, Beijing 100730, China.
Li
L
Wang
Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, Beijing 100730, China.
Hua
H
Chen
Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, Beijing 100730, China.
Wen-Jie
WJ
Zheng
Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, Beijing 100730, China.
Yun-Yun
YY
Fei
Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, Beijing 100730, China.
Fu-Lin
FL
Tang
Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, Beijing 100730, China.
Yong-Zhe
YZ
Li
Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, Beijing 100730, China.
Feng-Chun
FC
Zhang
Department of Immunology, School of Basic Medicine, Peking Union Medical College, and Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing 100005, China.
Wei
W
He
Department of Immunology, School of Basic Medicine, Peking Union Medical College, and Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing 100005, China.
Xue-Tao
XT
Cao
Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, Beijing 100730, China.
Xuan
X
Zhang
D000293:Adolescent; D000328:Adult; D000888:Antibodies, Anti-Idiotypic / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology*; D023201:CD40 Ligand / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007378:Interleukins / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008181:Lupus Nephritis / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000235:genetics / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics* / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism; D060149:Tetraspanin 30 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D055815:Young Adult; D000098546:Interleukin-21
D000888:Antibodies, Anti-Idiotypic; C084103:BCL6 protein, human; C554586:CD63 protein, human; C527276:CXCR4 protein, human; D007378:Interleukins; D051560:Proto-Oncogene Proteins c-bcl-6; D019718:Receptors, CXCR4; D050791:STAT Transcription Factors; D060149:Tetraspanin 30; C044203:anti-IgM; D023201:CD40 Ligand; D019869:Phosphatidylinositol 3-Kinases; D000098546:Interleukin-21
Mediators Inflamm. 2012;2012:495934
23125486
J Immunol. 2007 Nov 1;179(9):5886-96
17947662
Nat Immunol. 2004 Sep;5(9):943-52
15300245
Gene. 2014 Mar 15;538(1):94-8
24434811
Expert Opin Ther Targets. 2009 Oct;13(10):1147-53
19670960
N Engl J Med. 2008 Feb 28;358(9):929-39
18305268
Nature. 1998 Jun 11;393(6685):591-4
9634237
Blood. 2000 Jun 1;95(11):3289-96
10828007
PLoS One. 2015 Apr 24;10(4):e0125340
25909640
Traffic. 2008 Apr;9(4):540-58
18182005
J Exp Med. 2001 Jul 2;194(1):45-56
11435471
Arthritis Rheum. 2010 Nov;62(11):3436-46
20722038
Cell Mol Immunol. 2015 Jan;12(1):31-9
25088225
J Immunol. 2009 Sep 1;183(5):3139-49
19666691
Kidney Int. 2005 May;67(5):1772-84
15840024
J Biol Chem. 2005 Apr 29;280(17 ):17408-14
15611059
Nephrol Dial Transplant. 2011 Feb;26(2):498-508
20709738
Blood. 1999 Nov 1;94(9):2990-8
10556181
J Immunol. 2011 Mar 1;186(5):2800-8
21270405
Microbiol Immunol. 2009 Nov;53(11):629-35
19903263
J Recept Signal Transduct Res. 2009 Dec;29(6):293-8
19929250
Int J Mol Med. 2005 Oct;16(4):609-15
16142394
Sci Transl Med. 2014 Jul 23;6(246):246ra99
25101889
J Cell Mol Med. 2016 May;20(5):949-61
26871266
Immunity. 2006 Dec;25(6):977-88
17174120
J Exp Med. 2010 Jan 18;207(1):155-71
20048285
Ann N Y Acad Sci. 2007 Sep;1110:590-601
17911475
J Immunol. 2009 Apr 1;182(7):4448-58
19299746
J Exp Med. 1999 May 3;189(9):1461-6
10224286
Nature. 1998 Jun 11;393(6685):595-9
9634238
J Transl Med. 2012 Dec 18;10:251
23244336
FASEB J. 1999 Oct;13(13):1699-710
10506573
J Immunol. 2003 Mar 15;170(6):3392-400
12626600
Nature. 1996 Aug 15;382(6592):635-8
8757135
J Immunol. 2000 Nov 15;165(10):5970-9
11067960
J Immunol. 2006 Dec 15;177(12):8381-92
17142735
J Immunol. 2004 Nov 1;173(9):5361-71
15494482
J Immunol. 2012 Apr 15;188(8):3700-8
22422878
Cancer Metastasis Rev. 2010 Dec;29(4):709-22
20839032
J Immunol. 2000 May 15;164(10):5010-4
10799853
Clin Exp Rheumatol. 2015 Nov-Dec;33(6):863-70
26320881
FEBS Lett. 1998 Apr 17;426(2):271-8
9599023