Menke Julia, Rabacal Whitney A, Byrne Katelyn T, Iwata Yasunori, Schwartz Melvin M, Stanley E Richard, Schwarting Andreas, Kelley Vicki R
Laboratory of Molecular Autoimmune Disease, Renal Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.
J Am Soc Nephrol. 2009 Dec;20(12):2581-92. doi: 10.1681/ASN.2009050499. Epub 2009 Nov 19.
Macrophages mediate kidney disease and are prominent in a mouse model (MRL-Fas(lpr)) of lupus nephritis. Colony stimulating factor-1 (CSF-1) is the primary growth factor for macrophages, and CSF-1 deficiency protects MRL-Fas(lpr) mice from kidney disease and systemic illness. Whether this renoprotection derives from a reduction of macrophages and whether systemic CSF-1, as opposed to intrarenal CSF-1, promotes macrophage-dependent lupus nephritis remain unclear. Here, we found that increasing systemic CSF-1 hastened the onset of lupus nephritis in MRL-Fas(lpr) mice. Using mutant MRL-Fas(lpr) strains that express high, moderate, or no systemic CSF-1, we detected a much higher tempo of kidney disease in mice with the highest level of CSF-1. Furthermore, we uncovered a multistep CSF-1-dependent systemic mechanism central to lupus nephritis. CSF-1 heightened monocyte proliferation in the bone marrow (SSC(low)CD11b(+)), and these monocytes subsequently seeded the circulation. Systemic CSF-1 skewed the frequency of monocytes toward "inflammatory" (SSC(low)CD11b(+)Ly6C(high)) and activated populations that homed to sites of inflammation, resulting in a more rapid accumulation of intrarenal macrophages (CD11b(+)CSF-1R(+) or CD68(+)) that induced apoptosis of tubular epithelial cells, damaging the kidney. In humans, we found increased levels of CSF-1 in the serum, urine, and kidneys of patients with lupus compared with healthy controls. Furthermore, serum and urine CSF-1 levels correlated with lupus activity, and intrarenal CSF-1 expression correlated with the histopathology activity index of lupus nephritis. Taken together, circulating CSF-1 is a potential therapeutic target for lupus nephritis.
巨噬细胞介导肾脏疾病，在狼疮性肾炎的小鼠模型（MRL-Fas(lpr)）中巨噬细胞很突出。集落刺激因子-1（CSF-1）是巨噬细胞的主要生长因子，CSF-1缺乏可保护MRL-Fas(lpr)小鼠免受肾脏疾病和全身性疾病的影响。这种肾脏保护作用是否源于巨噬细胞数量的减少，以及与肾内CSF-1相对的全身性CSF-1是否促进巨噬细胞依赖性狼疮性肾炎仍不清楚。在此，我们发现增加全身性CSF-1会加速MRL-Fas(lpr)小鼠狼疮性肾炎的发病。使用表达高水平、中等水平或无全身性CSF-1的突变MRL-Fas(lpr)品系，我们在CSF-1水平最高的小鼠中检测到肾脏疾病的进展速度要快得多。此外，我们发现了一个多步骤的、依赖CSF-1的全身性机制，它是狼疮性肾炎的核心。CSF-1增强了骨髓中单核细胞（SSC(low)CD11b(+)）的增殖，这些单核细胞随后进入循环。全身性CSF-1使单核细胞的频率偏向“炎症性”（SSC(low)CD11b(+)Ly6C(high)）并激活归巢到炎症部位的细胞群，导致肾内巨噬细胞（CD11b(+)CSF-1R(+)或CD68(+)）更快积累，从而诱导肾小管上皮细胞凋亡，损害肾脏。在人类中，我们发现与健康对照相比，狼疮患者血清、尿液和肾脏中的CSF-1水平升高。此外，血清和尿液CSF-1水平与狼疮活动相关，肾内CSF-1表达与狼疮性肾炎的组织病理学活动指数相关。综上所述，循环中的CSF-1是狼疮性肾炎潜在的治疗靶点。
