Activated renal macrophages are markers of disease onset and disease remission in lupus nephritis
Activated renal macrophages are markers of disease onset and disease remission in lupus nephritis
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DOI：
10.4049/jimmunol.180.3.1938
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发表时间：
2008-02-01
影响因子：
4.4
通讯作者：
Davidson, Anne
中科院分区：
文献类型：
--
作者：
Schiffer, Lena;Bethunaickan, Ramalingam;Davidson, Anne
CTLA4Ig和抗cd40l共刺激阻断联合单剂量环磷酰胺可诱导NZB/W F(1)小鼠系统性红斑狼疮肾炎缓解。为了了解缓解和即将复发的机制，我们检测了61种炎症分子在不同疾病阶段治疗小鼠和未治疗小鼠的灌注肾脏中的表达谱。使用流式细胞术和免疫组织化学的进一步研究使我们能够确定几个关键标记物的细胞起源。我们发现只有一组有限的炎症介质在肾小球免疫复合物沉积后但在蛋白尿发作之前在肾脏中表达。肾盂内淋巴聚集体的形成先于炎症细胞侵入肾脏。调节分子在疾病过程的早期和缓解期间表达，但不能阻止活动性炎症的不可避免的进展。增殖性肾小球肾炎和蛋白尿的发病与肾内皮的激活、介导肾小球细胞浸润的趋化因子的表达以及迁移到肾脏不同地形区域但表达相似炎症细胞因子的活化树突状细胞和巨噬细胞的浸润有关。增加间隙。巨噬细胞的浸润和进行性小管损伤，表现为脂钙素-2的产生，发生在疾病过程的后期。对治疗小鼠的研究发现，II型（M2b）活化的巨噬细胞是缓解诱导和即将复发的标志，并提示系统性红斑狼疮肾炎的治疗应包括防止单核细胞活化及其向肾脏迁移的策略。
Costimulatory blockade with CTLA4Ig and anti-CD40L along with a single dose of cyclophosphamide induces remission of systemic lupus erythematosus nephritis in NZB/W F(1) mice. To understand the mechanisms for remission and for impending relapse, we examined the expression profiles of 61 inflammatory molecules in the perfused kidneys of treated mice and untreated mice at different stages of disease. Further studies using flow cytometry and immunohistochemistry allowed us to determine the cellular origins of several key markers. We show that only a limited set of inflammatory mediators is expressed in the kidney following glomerular immune complex deposition but before the onset of proteinuria. Formation of a lymphoid aggregate in the renal pelvis precedes the invasion of the kidney by inflammatory cells. Regulatory molecules are expressed early in the disease process and during remission but do not prevent the inevitable progression of active inflammation. Onset of proliferative glomerulonephritis and proteinuria is associated with activation of the renal endothelium, expression of chemokines that mediate glomerular cell infiltration, and infiltration by activated dendritic cells and macrophages that migrate to different topographical areas of the kidney but express a similar profile of inflammatory cytokines. Increasing interstitial. infiltration by macrophages and progressive tubular damage, manifested by production of lipocalin-2, occur later in the disease process. Studies of treated mice identify a type II (M2b)-activated macrophage as a marker of remission induction and impending relapse and suggest that therapy for systemic lupus erythematosus nephritis should include strategies that prevent both activation of monocytes and their migration to the kidney.