Properdin homeostasis requires turnover of the alternative complement pathway.
Properdin is a plasma protein and is also released from neutrophil granules following stimulation. At inflammatory sites it can bind bacteria and apoptotic bodies to trigger alternative pathway (AP) activation. Principles governing properdin homeostasis are unknown. We monitored properdin during AP activation and in complement-deficient mice. There was a >90% reduction of properdin in the Crry single-knockout mice (Crry SKO). These membrane complement regulatory protein-deficient mice feature accelerated AP turnover, leading to reduced C3 and fB. Injecting cobra venom factor into wild-type mice activated the AP and led to the consumption of C3, fB, and properdin. However, and unexpectedly, properdin was also deficient in C3(-/-), fB(-/-), and fD(-/-) mice. It was present in C1q(-/-), C4(-/-), and C5(-/-) mice. These findings implicate AP turnover in the maintenance of basal levels of properdin in the blood. To explore the mechanism, classical pathway-activating immune complexes were infused. Within 10 min, properdin was partially restored in fB(-/-) but not in C3(-/-) mice. Markedly reduced properdin in mice deficient in an AP component and its partial restoration by activating C3 suggest a requirement for continuous C3 activation via AP tickover to maintain properdin homeostasis. The mechanism underlying this C3-dependent process was not identified. Engagement of C3a and C5a receptors was ruled out. These findings represent an instructive example of how a positive regulator of an innate immune recognition and effector pathway is controlled. A rationale for such a means to supply properdin for immune reactions is proposed.
Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Xiaobo
X
Wu
Thomas Q
TQ
Xu
John P
JP
Atkinson
D000818:Animals; D015926:Complement C3a; D015936:Complement C5a; D003170:Complement Pathway, Alternative; D006706:Homeostasis; D007113:Immunity, Innate; D007155:Immunologic Factors; D051379:Mice; D018345:Mice, Knockout; D011414:Properdin / Q000378:metabolism*
D007155:Immunologic Factors; D011414:Properdin; D015926:Complement C3a; D015936:Complement C5a