Pathogenic anti-DNA antibodies modulate gene expression in mesangial cells: involvement of HMGB1 in anti-DNA antibody-induced renal injury.
Although anti-DNA antibodies have been decisively linked to the pathogenesis of lupus nephritis, the mechanisms have not been conclusively determined. Recently, we reported that anti-DNA antibodies may contribute to kidney damage by upregulation of proinflammatory genes in mesangial cells (MC), a process involving both Fc receptor-dependent and independent pathways. In investigating the mechanism by which pathogenic anti-DNA antibodies modulate gene expression in MC, we found that the pathogenic anti-DNA antibody 1A3F bound to high mobility group binding protein 1 (HMGB1), an endogenous ligand for TLR2/4 and RAGE (receptor for advanced glycation end products). Interestingly, HMGB1 treatment of MC induced a similar pattern of genes as stimulation with 1A3F. Furthermore, HMGB1 and 1A3F exhibited a synergistic proinflammatory effect in the kidney, where increased expression of HMGB1 was found in lupus patients but not in patients with other types of renal disease. TLR2/Fc and RAGE/Fc inhibited the proinflammatory effects of 1A3F on MC. Finally, we found enhanced susceptibility of lupus prone MRL-lpr/lpr (MRL/lpr) as compared to normal BALB/c derived MC to pathogenic anti-DNA antibody and LPS stimulation (in particular enhanced chemokine synthesis), in addition to significantly increased expression of TLR4. Our results suggest that gene upregulation in MC induced by nephritogenic anti-DNA antibodies is TLR2/4 and RAGE-dependent. Finally, HMGB1 may act as a proinflammatory mediator in antibody-induced kidney damage in systemic lupus erythematosus (SLE).
Qing
Xiaoping
X
The Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, NY, USA.
Pitashny
Milena
M
Thomas
David B
DB
Barrat
Franck J
FJ
Hogarth
Mark P
MP
Putterman
Chaim
C
D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology*; D015536:Down-Regulation / Q000276:immunology; D005260:Female; D015870:Gene Expression; D024243:HMGB1 Protein / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008181:Lupus Nephritis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D050527:Mesangial Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D019463:Mice, Inbred MRL lpr; D020928:Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000276:immunology / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology
D000974:Antibodies, Antinuclear; D024243:HMGB1 Protein; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C498977:Mok protein, mouse; D020928:Mitogen-Activated Protein Kinases