Contribution of Adipose-derived Factor D/Adipsin to Alternative Pathway Complement Activation: Lessons from Lipodystrophy
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 adi...
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Published in | The Journal of immunology (1950) Vol. 200; no. 8; pp. 2786 - 2797 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
12.03.2018
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Online Access | Get full text |
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Summary: | 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: First, to what degree does adipose
tissue contribute to circulating FD levels? Second, 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
lipodystrophy, a 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 wildtype 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 ~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. Further, this observation
highlights the potential importance of obtaining near complete inhibition of FD
in treating alternative complement activation in various autoimmune and
inflammatory human diseases. |
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ISSN: | 0022-1767 1550-6606 |
DOI: | 10.4049/jimmunol.1701668 |