TLR4 up-regulation at protein or gene level is pathogenic for lupus-like autoimmune disease.
TLR4 is the receptor for the Gram-negative bacterial cell wall component LPS. TLR4 signaling is controlled by both positive and negative regulators to balance optimal immune response and potential sepsis. Unchecked TLR4 activation might result in autoimmune diseases, a hypothesis that has not been formally resolved. In this study, we found that TLR4 signaling to LPS can be positively enforced by expressing gp96 on cell surfaces through the chaperone function of, but not the direct signaling by, gp96; TLR4 as well as the commensal flora are essential for the production of anti-dsDNA Ab and the immune complex-mediated glomerulonephritis in transgenic mice that express surface gp96. Moreover, a similar constellation of autoimmunity was evident in mice that encode multiple copies of tlr4 gene. Our study has revealed that increased TLR4 signaling alone without exogenous insult can break immunological tolerance. It provides a strong experimental evidence for TLR4 dysregulation as an etiology of lupus-like renal disease.
Liu
Bei
B
Department of immunology, Center for Immunotherapy of Cancer and Infectious Diseases, University of Connecticut School of Medicine, Farmington, CT 06030-1601, USA.
Yang
Yi
Y
Dai
Jie
J
Medzhitov
Ruslan
R
Freudenberg
Marina A
MA
Zhang
Ping L
PL
Li
Zihai
Z
D000818:Animals; D001419:Bacteria / Q000276:immunology; D002460:Cell Line; D002462:Cell Membrane / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005260:Female; D005784:Gene Amplification / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D008070:Lipopolysaccharides / Q000633:toxicity; D008181:Lupus Nephritis / Q000235:genetics* / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D012995:Solubility; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D015854:Up-Regulation / Q000235:genetics* / Q000276:immunology*
D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C053387:endoplasmin