Contribution of Adipose-Derived Factor D/Adipsin to Complement Alternative Pathway Activation: Lessons from Lipodystrophy
Contribution of Adipose-Derived Factor D/Adipsin to Complement Alternative Pathway Activation: Lessons from Lipodystrophy
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DOI：
10.4049/jimmunol.1701668
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发表时间：
2018-04-15
影响因子：
4.4
通讯作者：
Harris, Charles A.
中科院分区：
文献类型：
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作者：
Wu, Xiaobo;Hutson, Irma;Harris, Charles A.
D因子(Fd)是补体替代途径(AP)的重要组成部分。它是一个有吸引力的药物靶点，因为它是一种在血液中循环的AP特异性蛋白酶。补体激活途径的大部分成分是由肝脏产生的，但FD在脂肪组织中高度表达。两个关键问题是：1)脂肪组织在多大程度上对循环FD水平有贡献；2)什么量的FD足以维持功能性AP？为了解决这些问题，我们研究了一种新的完全性脂肪营养不良(LD)小鼠品系、部分LD的FLD小鼠、FD缺陷小鼠和脂肪营养不良患者的样本。LD小鼠血清中未检测到FD，也表现出极小的AP功能。用纯化的FD重建，血清混合实验，以及对部分LD小鼠的研究都表明，低水平的血清FD足以维持小鼠系统中正常的AP活动。将野生型脂肪前体移植到LD小鼠体内的实验进一步支持了这一结论。我们的结果表明，小鼠血清中几乎所有的FD都来自脂肪组织。相比之下，先天性全身性腰椎间盘突出症患者血清中的FD水平下降了近50%。我们的研究进一步证明，在人类和小鼠中，相对少量的血清FD足以促进显着的时间依赖性AP活动。此外，这一观察结果强调了在治疗各种自身免疫性和炎症性人类疾病的替代补体激活方面获得几乎完全抑制FD的潜在重要性。
Factor D (FD) is an essential component of the complement alternative pathway (AP). It is an attractive pharmaceutical target because it is an AP-specific protease circulating in blood. Most components of the complement activation pathways are produced by the liver, but FD is highly expressed by adipose tissue. Two critical questions are: 1) to what degree does adipose tissue contribute to circulating FD levels and 2) what quantity of FD is sufficient to maintain a functional AP? To address these issues, we studied a novel mouse strain with complete lipodystrophy (LD), the fld mouse with partial LD, an FD-deficient mouse, and samples from lipodystrophic patients. FD was undetectable in the serum of LD mice, which also showed minimal AP function. Reconstitution with purified FD, serum mixing experiments, and studies of partial LD mice all demonstrated that a low level of serum FD is sufficient for normal AP activity in the mouse system. This conclusion was further supported by experiments in which wild-type adipose precursors were transplanted into LD mice. Our results indicate that almost all FD in mouse serum is derived from adipose tissue. In contrast, FD levels were reduced similar to 50% in the sera of patients with congenital generalized LD. Our studies further demonstrate that a relatively small amount of serum FD is sufficient to facilitate significant time-dependent AP activity in humans and in mice. Furthermore, this observation highlights the potential importance of obtaining nearly complete inhibition of FD in treating alternative complement activation in various auto immune and inflammatory human diseases.