Contribution of Adipose-Derived Factor D/Adipsin to Complement Alternative Pathway Activation: Lessons from Lipodystrophy

Abstract

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 ∼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 autoimmune and inflammatory human diseases.

Be on Target: Strategies of Targeting Alternative and Lectin Pathway Components in Complement-Mediated Diseases

“…It has a relatively low mass concentration of 1–4 µg/mL in humans ( 147 – 149 ), which in combination with early reports showing that FD is the bottleneck of AP activity ( 140 ), led to the assumption that FD could be the best target to achieve AP inhibition. However, FD is a small protein of only 25 kDa, so, its molar concentration of 40–160 nM combined with its high turnover ( 139 ) suggest that high daily doses of a FD inhibitor would be required to achieve complete sustained inhibition.…”

“…Recent results also suggest that FD may not even be the bottleneck of AP activity. In the serum of FD-deficient mice, the addition of FD corresponding to only about 1–2% of the normal FD level was sufficient for normal AP activity in vitro ( 147 ). In a 3MC syndrome patient, whose serum contained mostly pro-FD, some AP activity was still present ( 72 ), although lower than the normal level ( 134 ).…”

Adipose Tissue is a Critical Regulator of Osteoarthritis

“…It is important to note that LD mice also lack other signaling pathways, such as the alternative complement pathway. LD mice have an absence of adipsin, or complement factor D, which cleaves factor B to initiate alternative complement pathway activity (12). Previous studies have demonstrated a protective effect of adipsin deficiency on both spontaneous and post-traumatic OA pathogenesis (13,37), so it is unclear if adipsin deficiency is the protective adipokine mechanism modulating joint damage in the present studies.…”

“…The exact contribution of the adipokine signaling network in OA has been difficult to determine due to the complex interactions among metabolic, biomechanical, and inflammatory factors related to obesity (11). To date, the link between increased adipose tissue mass and OA pathogenesis has largely been correlative (7,8,12) and as such, the direct effect of adipose tissue has been difficult to separate from other factors such as dietary composition or excess body mass in the context of obesity, which is most commonly derived from excessive nutrition (3,7,8). Leptin, a pro-inflammatory adipokine and satiety hormone, is secreted proportionally to adipose tissue mass and is the most consistently increased mediator reported in the pathogenesis of obesity-induced OA (1).…”

“…The LD model system affords the unique opportunity to directly examine the effects of adipose tissue and its secretory factors on musculoskeletal pathology without the confounding effect of diet (14,15). LD mice completely lack adipose tissue depots, demonstrate similar body mass to WT controls on a chow diet, but exhibit metabolic dysfunction similar to mice with obesity (12,(14)(15)(16)(17). This allows us to eliminate the factor of loading due to body mass on joint damage and directly test the effects of fat and factors secreted by fat on musculoskeletal tissues.…”