TY - JOUR
T1 - Featured Article
T2 - Interactions of surface-expressed TLR-4 and endosomal TLR-9 accelerate lupus progression in anti-dsDNA antibody transgenic mice
AU - Lee, Tai Ping
AU - Huang, Jason C.
AU - Liu, Chi Jui
AU - Chen, Hsiu Jung
AU - Chen, Yih Horng
AU - Tsai, Yi Ting
AU - Yang, Winnie
AU - Sun, Kuang Hui
N1 - Funding Information:
The work was supported by grants from the National Science Council (98-2320-B-010-001-MY3, 100-2321-B-010-017, 101-2321-B-010-005) and the Ministry of Education, Aiming for the Top University Plan, ROC. In addition, this work was supported by grants from the Department of Education and Research, Taipei City Hospital, Taipei, Taiwan (99TPECH08, 10101-62-002, 10201-62-013). The authors have no financial conflicts of interest.
PY - 2014/6
Y1 - 2014/6
N2 - The hallmark of systemic lupus erythematosus (SLE) is the presence of high levels of anti-double-stranded DNA autoantibody (anti-dsDNA) in sera. In addition, pathogen infections coincide frequently with the occurrence of lupus. Our study was designed to investigate the contribution of anti-dsDNA, extracellular and intracellular Toll-like receptors (TLRs), a family of pattern-recognition receptors for sensing invading pathogens, in the pathogenesis of lupus. Although cell surface-expressed TLR4 may promote lupus progression, intracellular nucleic acid-sensing TLR9 plays either stimulatory or protective roles in different murine lupus models. To examine the role of TLR4, TLR9, and anti-dsDNA in SLE, we generated transgenic mice carrying anti-dsDNA antibody transgene and challenged the mice with TLR4- and TLR9-agonists, lipopolysaccharides (LPS), and CpG oligodeoxynucleotide (CpG ODN1826 and 2216), respectively. Splenocytes from these mice were found to secrete higher levels of interleukin-10 (IL-10) and anti-dsDNA when treated with a combination of TLR4 and TLR9 agonists (LPS + CpG). In addition, the transgenic mice were intraperitoneally administered with CpG or combined CpG and LPS to determine whether extracellular TLR4 and intracellular TLR9 activations could affect lupus progression in vivo. It was found that serum levels of anti-dsDNA antibodies and interferon-alpha were higher in CpG + LPS-treated transgenic mice than those in non-transgenic mice. Besides, elevated levels of proteinuria, blood urine nitrogen, and immune complex depositions in kidney were found in treated transgenic mice. Anti-dsDNA and simultaneous activation of surface-expressed TLR4 and endosomal TLR9 are crucial to promote the lupus progression.
AB - The hallmark of systemic lupus erythematosus (SLE) is the presence of high levels of anti-double-stranded DNA autoantibody (anti-dsDNA) in sera. In addition, pathogen infections coincide frequently with the occurrence of lupus. Our study was designed to investigate the contribution of anti-dsDNA, extracellular and intracellular Toll-like receptors (TLRs), a family of pattern-recognition receptors for sensing invading pathogens, in the pathogenesis of lupus. Although cell surface-expressed TLR4 may promote lupus progression, intracellular nucleic acid-sensing TLR9 plays either stimulatory or protective roles in different murine lupus models. To examine the role of TLR4, TLR9, and anti-dsDNA in SLE, we generated transgenic mice carrying anti-dsDNA antibody transgene and challenged the mice with TLR4- and TLR9-agonists, lipopolysaccharides (LPS), and CpG oligodeoxynucleotide (CpG ODN1826 and 2216), respectively. Splenocytes from these mice were found to secrete higher levels of interleukin-10 (IL-10) and anti-dsDNA when treated with a combination of TLR4 and TLR9 agonists (LPS + CpG). In addition, the transgenic mice were intraperitoneally administered with CpG or combined CpG and LPS to determine whether extracellular TLR4 and intracellular TLR9 activations could affect lupus progression in vivo. It was found that serum levels of anti-dsDNA antibodies and interferon-alpha were higher in CpG + LPS-treated transgenic mice than those in non-transgenic mice. Besides, elevated levels of proteinuria, blood urine nitrogen, and immune complex depositions in kidney were found in treated transgenic mice. Anti-dsDNA and simultaneous activation of surface-expressed TLR4 and endosomal TLR9 are crucial to promote the lupus progression.
KW - anti-double-stranded DNA autoantibody
KW - CpG oligodeoxynucleotide
KW - lipopolysaccharides
KW - Systemic lupus erythematosus
KW - Toll-like receptors
UR - http://www.scopus.com/inward/record.url?scp=84903374035&partnerID=8YFLogxK
U2 - 10.1177/1535370214525299
DO - 10.1177/1535370214525299
M3 - Article
C2 - 24719374
AN - SCOPUS:84903374035
SN - 1535-3702
VL - 239
SP - 715
EP - 723
JO - Experimental Biology and Medicine
JF - Experimental Biology and Medicine
IS - 6
ER -