Brown Heather J, Lock Helen R, Wolfs Tim G A M, Buurman Wim A, Sacks Steven H, Robson Michael G
Department of Nephrology and Transplantation, 5th Floor Thomas Guy House, Guy's Hospital, St. Thomas Street, London, UK.
J Am Soc Nephrol. 2007 Jun;18(6):1732-9. doi: 10.1681/ASN.2006060634. Epub 2007 Apr 25.
Autoimmune diseases such as glomerulonephritis are exacerbated by infection. This study examined the effect of the Toll-like receptor 4 (TLR4) ligand lipid A on the development of heterologous nephrotoxic nephritis. Administration of nephrotoxic antibody resulted in significant glomerular neutrophil infiltration and albuminuria only when a TLR4 ligand was administered simultaneously. The contribution of TLR4 on renal cells and circulating leukocytes was assessed. Bone marrow chimeras were constructed with TLR4 only on renal cells or bone marrow-derived cells. The administration of nephrotoxic serum and lipid A caused a neutrophil influx in both chimeric groups greater than in sham chimeras that were totally TLR4 deficient but significantly less than in sham chimeras that were totally TLR4 sufficient. Both chimeric groups had greater albuminuria than totally TLR4-deficient sham chimeras; however, the chimeras with TLR4 only on intrinsic renal cells had significantly less than the sham positive group. In situ hybridization showed expression of TLR4 mRNA in mesangial cells and glomerular epithelial cells. For investigation of the potential mechanism by which renal cells could contribute to disease exacerbation, mesangial cells were cultured and found to express mRNA for TLR4, and stimulation of wild-type and TLR4-deficient mesangial cells with LPS caused production of CXC chemokines by wild-type cells only. Treatment of chimeras with TLR4 present only on intrinsic renal cells with anti-CXCL1 and anti-CXCL2 antibody before disease induction significantly reduced renal neutrophil infiltration. These results show that TLR4 on both circulating leukocytes and intrinsic renal cells contributes to the inflammatory effects of antibody deposition within the glomerulus, which depends at least in part on the production of CXC chemokines by intrinsic renal cells.
诸如肾小球肾炎之类的自身免疫性疾病会因感染而加重。本研究检测了Toll样受体4（TLR4）配体脂多糖对异源性肾毒性肾炎发展的影响。仅当同时给予TLR4配体时，给予肾毒性抗体才会导致显著的肾小球中性粒细胞浸润和蛋白尿。评估了TLR4对肾细胞和循环白细胞的作用。构建了仅在肾细胞或骨髓来源细胞上表达TLR4的骨髓嵌合体。给予肾毒性血清和脂多糖后，两个嵌合组中的中性粒细胞流入均高于完全缺乏TLR4的假嵌合体，但显著低于完全具有TLR4的假嵌合体。两个嵌合组的蛋白尿均高于完全缺乏TLR4的假嵌合体；然而，仅在固有肾细胞上表达TLR4的嵌合体的蛋白尿显著少于假阳性组。原位杂交显示系膜细胞和肾小球上皮细胞中有TLR4 mRNA表达。为了研究肾细胞可能导致疾病加重的潜在机制，培养系膜细胞并发现其表达TLR4的mRNA，用脂多糖刺激野生型和TLR4缺陷型系膜细胞，结果只有野生型细胞产生CXC趋化因子。在疾病诱导前，用抗CXCL1和抗CXCL2抗体处理仅在固有肾细胞上表达TLR4的嵌合体，可显著减少肾中性粒细胞浸润。这些结果表明，循环白细胞和固有肾细胞上的TLR4均有助于肾小球内抗体沉积的炎症效应，这至少部分取决于固有肾细胞产生CXC趋化因子。
