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Proc Natl Acad Sci U S A. Nov 9, 2010; 107(45): 19444–19448.
Published online Oct 25, 2010. doi:  10.1073/pnas.1006608107
PMCID: PMC2984156

This article has been retractedRetraction in: Proc Natl Acad Sci U S A. 2011 June 21; 108(25): 10372    See also: PMC Retraction Policy

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.

Keywords: innate immunity, C3, neutrophil, regulators of complement activation

The complement system is an essential player in the immune response to many pathogens. Induction of inflammation, opsonization, and cell lysis are achieved by each of its three major pathways (1). The AP is an innate immune surveillance system that continuously turns over at a slow rate (2). In addition, the AP serves as a means to amplify the deposition of C3b on a target via its feedback loop. Such a mechanism to enhance complement activation requires strict regulation of the AP C3 convertase, which is carried out by plasma and membrane proteins that inhibit fluid phase activation and activation on normal self (13).

The AP was initially called the properdin pathway to emphasize the initiating role envisioned for this protein by its founders and to point out that it did not require antibody for activation (4). Subsequently, properdin was relegated to a more limited role as a positive regulator of the AP C3 convertase (1, 5). Recent reports, however, indicate that properdin may indeed bind directly to targets such as bacteria or apoptotic cells to both trigger and enhance AP activation (610). These observations are also congruent with its synthesis by and release from neutrophils. Therefore, properdin binding may serve as a pattern recognition receptor, being a nidus to form as well as to stabilize AP convertases at sites of infection (10).

The AP C3 convertase can be initiated by factor B (fB) binding to C3b to form the proenzyme C3bB (1, 2). Factor D (fD) then cleaves fB to form C3bBb, with liberation of Ba. Properdin binds to and stabilizes this enzyme complex in which C3b is covalently bound to a target, and Bb contains the serine protease catalytic domain. The half-life of the AP C3 convertase is increased 5- to 10-fold through its association with properdin (5). The AP C3 convertase cleaves C3 to C3b and C3a and thus serves as a feedback or amplification loop to generate more convertases.

Basal “tickover” of the AP has been recognized since the pioneering work of the Fearon and Austen, Pangburn and Müller–Eberhard, and Lachmann groups (1, 2, 5) and the clinical studies of Alper, Rosen, and coworkers (11, 12). The latter group described a patient with a deficiency of the plasma regulator factor I (fI) who demonstrated markedly enhanced AP tickover with almost complete consumption of C3 and fB (11). This pathologic activation was corrected by serum transfusion or infusion of the purified protein (12). Subsequently, a deficiency of the major inhibitor of AP in plasma, fH, was also shown to lead to a similar phenotype in man (1315), mouse (16), and pig (17). More recently, a deficiency of a major membrane regulator of C3b in the mouse, Crry, was also shown to cause accelerated AP turnover, resulting in C3 and fB levels of approximately one-third of normal (1820). Crry and fH are cofactor proteins for the proteolytic cleavage of C3b by the serine protease fI. This limited proteolysis permanently inactivates C3b relative to its ability to engage fB and therefore is critical in regulating the AP's feedback loop. These data highlight the role of plasma and membrane inhibitors in maintaining homeostasis of the AP.

Unlike most other complement plasma proteins, properdin is not synthesized by hepatocytes (2123). Instead, peripheral blood leukocytes, including neutrophils and monocytes/macrophages as well as T lymphocytes, synthesize properdin (21, 22). Properdin is stored in the secondary granules of human neutrophils (24). The source of blood properdin is unknown but thought to be derived from bone marrow-derived cells (24). Properdin release from secondary granules at the site of inflammatory injury would facilitate opsonization of the pathogen. However, principles governing properdin homeostasis in vivo are unknown.

In these studies, we used mouse models to first show that properdin was depleted in states of excessive AP turnover. Second, properdin was unexpectedly also reduced in C3-, fB-, and fD-deficient mice, implicating physiologic AP turnover in maintaining properdin homeostasis in plasma. In particular, we propose that a fragment of C3 orchestrates properdin release in a process designed to limit intravascular AP activation but to promote AP activation at inflammatory sites.


Properdin Consumption in Crry-Deficient Mice.

Crry is a widely expressed 65-kDa transmembrane protein that regulates complement activation on host cells (25, 26). The Crry−/− mouse is an embryonic lethal phenotype due to maternal complement activation on placental tissue (27). However, Crry−/−fB−/− and Crry−/−C3−/− mice survive, establishing that the AP mediates embryo demise (28). Using maternal breeding partners with reduced AP-activating capacity, Crry-deficient mice were generated with a WT genetic background for C3 and fB (the Crry single-knockout mice, Crry SKO) (18). Crry SKO mice have reduced C3 and fB due to accelerated membrane turnover of the AP (18, 19). This C3 consumption in the Crry SKO mouse is abrogated in Crry−/−fB−/− mice (18). Our initial aims were to determine if properdin is consumed during heightened AP turnover and to check its concentration in mice lacking AP function secondary to C3, fB, or fD deficiency.

We therefore assessed properdin levels in Crry SKO mice whose C3 and fB levels are about one-third of WT secondary to excessive AP activation (18). Properdin was not detectable in these mice, suggesting that it was consumed (Fig. 1A and Fig. S1). Moreover, properdin was also reduced 50–70% in Crry+/− mice, again likely secondary to an increase in AP activation on cells haploinsufficient for this regulator (Fig. 1A). As the concentration of properdin is at least two logs less than C3, a modest increase in AP turnover would be sufficient to deplete properdin. Consistent with the preceding results, injection of CVF into WT mice to induce AP turnover depleted properdin (Fig. 1B). Properdin concentrations returned to baseline by day 7 after CVF treatment, coinciding with the near normalization of C3. In contrast to Crry−/− mice, DAF−/− mice had similar levels of properdin as WT (Fig. 2A and Fig. S1A), indicating that DAF (CD55) is not as critical as Crry relative to membrane regulation of the AP (18, 20). The Cr2−/− mice, lacking both complement receptor one (CR1) and complement receptor two (CR2), also had normal levels of properdin (Fig. 2A and Fig. S1A). Properdin mRNA, assessed by RT-PCR using bone marrow-derived cells, was similar in WT and Crry SKO mice (Fig. 2B). These findings establish that properdin deficiency in Crry SKO mice is caused by enhanced AP turnover.

Fig. 1.
Properdin consumption in mice with accelerated AP turnover. (A) Crry-deficient mice. In this and subsequent graphics, detection of properdin in WT, Crry+/−, and Crry SKO mice was by a pull-down assay using protein A-conjugated Sepharose 4B followed ...
Fig. 2.
Properdin protein concentrations and mRNA levels in complement-deficient mice. (A) DAF−/− and Cr2−/− mice (representative of six for each type). (B) Properdin and GAPDH mRNAs in WT, C3−/−, and Crry SKO mice ...

Maintenance of Properdin in Blood Requires Physiologic AP Turnover.

In parallel with the studies on properdin consumption in Crry-deficient mice, we measured the concentration of properdin in other complement-deficient mice. Unexpectedly, in our standard assay it was below detection limits in C3−/−, fB−/−, and fD−/− mice (Fig. 3A and Fig. S1B). Properdin was normal in C5−/− mice and elevated in C1q−/− and C4−/− mice (Fig. 3 A and B and Fig. S1B). These findings point to turnover of the AP, but not the CP or membrane attack complex, as being required for maintenance of physiologic concentrations of properdin. This hypothesis was supported by the observation that properdin was not detectable in Crry−/−C3−/−, Crry−/−fB−/−, or Crry−/− fD−/− mice, which also lack a functioning AP (Fig. 3C and Fig. S2). These data strengthen the argument favoring a role for AP activation in properdin homeostasis, and argue against the possibility of a low-affinity interaction between C3 and properdin, analogous to C1q and Ig (2931), being required to maintain properdin in the blood, as Crry−/−fB−/− and Crry−/−fD−/− mice have normal C3 levels (Fig. 3C and Fig. S2).

Fig. 3.
Properdin deficiency in mice with a defect in AP activation. (A) Properdin was determined in WT and complement-deficient mice. This experiment is representative of 12 C3−/−, 9 fB−/−, 9 fD−/−, 8 C4−/− ...

The possibility of a biosynthetic defect was also investigated. The properdin gene is located on the X chromosome (32) and is intact in the C3−/−, fB−/−, and fD−/− mice based on having the expected properdin mRNA concentrations in the bone marrow (Fig. 2 B and C). Also, the concentration of C3 and fB was normal in fD-, C4-, and C1q-deficient mice (Fig. S3).

Effect of Serum Transfer and Bone Marrow Transplantation on Properdin in Crry SKO and C3−/− Mice.

We next transferred i.v. 200 μL of WT serum (equivalent to ~25% of total serum volume) into C3−/− and Crry SKO mice (Fig. 4A). In kinetic analyses, the quantity of properdin detected was roughly proportional to that of C3 in a C3−/− host; however, if WT serum was transferred to Crry SKO mouse, there was a trace amount of properdin detected, consistent with accelerated consumption (Fig. 4 A and B and Fig. S4). This conclusion is also supported by the rapid accumulation of the C3 α2 fragment in Crry SKO mice following WT serum transfer (Fig. S5).

Fig. 4.
Properdin reconstitution through serum infusion or bone marrow transplantation. (A) Serum infusion. Wild-type serum (200 μL) was transferred to Crry SKO or C3−/− mice. At the time points indicated, samples were harvested from the ...

WT bone marrow was also transplanted into irradiated C3−/− mice to generate chimeric mice. Reconstitution of the bone marrow was verified through genotyping (Fig. S6). However, properdin and C3 were undetectable (Fig. 4C). Thus, bone marrow cells were not capable of correcting properdin deficiency in C3−/− mice. These findings further suggest that a defect in biosynthesis does not account for properdin deficiency in Crry SKO and C3−/− mice. Instead, they are consistent with an inability of properdin to be released from storage sites and/or to gain access to the circulation.

Properdin Release by Activation of C3.

We next asked if properdin deficiency in fB−/− mice was due to a defect in release of properdin from myeloid-derived cells. Factor B-deficient mice have modestly elevated C3 levels, presumably secondary to a lack of continuous turnover of the AP (33, 34). The classical pathway was activated by injecting immune complexes. In fB−/− mice, C3 was activated as evidenced by a 20–30% reduction of the C3 α-chain (Fig. 5A) and by the pattern of IC deposition in the spleen (Figs. S7A and S8; also, see below). Properdin was assessed in these mice in which the classical pathway was activated by IC. Ten minutes after infusion, properdin was present in fB−/− mice (Fig. 5A). In four such experiments, properdin remained detectable for 1 h but was gone by 3 h. Maximal release was early (10–30 min). The concentrations attained in blood varied from ~10% (Figs. S9 and S10E) to nearly 100% of normal (Fig. 5A). If the AP activator zymosan was used in fB−/− mice, properdin was not observed in the circulation (Fig. S9).

Fig. 5.
Properdin reconstitution in fB−/− but not C3−/− mice after injection of classical pathway-activating immune complexes (IC). (A) Effect of IC on properdin in fB−/− mice. Peroxidase-rabbit anti-peroxidase ...

To determine if C3 activation was the critical step in promoting properdin release, IC activation of the complement system was assessed in C3−/− mice. In contrast to its effect in fB−/− mice, there was no increase in properdin in C3−/− mice (Fig. 5B). These findings suggest that C3 activation is necessary for maintenance of properdin levels in plasma. They also further rule out a role for Fcγ receptors in this process.

Importantly, the classical pathway functioned normally in fB−/− mice as evidenced by IC deposition in the marginal zone and follicular areas of the spleen, a C3b-dependent process (Fig. S7A) (35). At 30 min, the IC are located in a circle outside the marginal zone. By 3 h, they have passed through the marginal zone to form a rim inside the follicle. At 24 h, they condense to form clusters in the FDC area. This is the same pattern observed in WT mice (Fig. S8). By 3 h the IC have moved from outside to inside the follicle. In Fig. S8, the marginal zone Moma-1 positive macrophages are also labeled (red), which facilitates monitoring the migration of the complement fixing IC (green). These findings indicate that in WT and fB−/− mice, the IC activated complement similarly as evidenced by their complement-dependent migration into the follicles (35).

To further verify the complement dependence of the IC deposition, FACS analysis was used to measure marginal B-cell trapping of IC in the spleen. As expected, there was a defect of IC deposition in the splenic marginal zone B cells of C3−/− and Cr2−/− mice; however, IC deposition in fB−/− mice was comparable to those of WT mice (Fig. S7B). In agreement with findings in C3−/− mice, IC deposition on B lymphocytes of CP-deficient mice (C1q−/− or C4−/−) was defective (Fig. S8B). The immunohistochemical and FACS analyses establish that C3 activation via the CP occurred in the AP-deficient mice.

Mechanism of Properdin Release Does Not Involve the C3a and/or C5a Receptor.

We initially speculated that properdin release was mediated by C5a binding to its receptor on hematopoietic cells. However, the normal level of properdin in the C5−/− mice ruled out this possibility (Fig. 3B). Mouse C3a receptor (C3aR) is also predominantly expressed by myeloid cells—specifically, macrophages, neutrophils, eosinophils, basophils, and mast cells (36). Therefore, engagement of this receptor was also a candidate for mediating properdin release. However, properdin levels in C3aR−/− mice were also comparable to those of WT controls (Fig. S10A), indicating that C3a is not the fragment of C3 responsible for triggering properdin release into the blood. These findings do not rule out the possibility that both could mediate the effect. Consequently, properdin levels were measured in C3aR−/−C5aR−/− DKO and C5aR−/− mice, and they were comparable to those in WT controls (Fig. S10 B and C). Also, properdin remained unchanged in C5−/− mice treated for 3 d with C3aR antagonist (Fig. S10D). In addition, there was no effect of C3aR antagonist treatment on immune complex-induced properdin release in the fB−/− mice (Fig. S10E). These findings suggest that properdin release does not appear to be related to C3a and/or C5a receptor engagement. iC3b and C3f are additional candidate C3 fragments for mediating properdin release (Discussion).


In the initial experiments, properdin was noted to be consumed in Crry SKO mice, which features accelerated spontaneous complement turnover as well as in WT mice if the AP was activated by CVF. However, properdin was also <10% of normal in C3-, fB-, and fD-deficient mice but normal in C1q-, C4-, and C5-deficient mice. These unanticipated findings implicated AP turnover in the mediating properdin homeostasis. Plasma properdin was partially restored by activating the classical pathway in fB−/− but not in C3−/− mice. Thus, as will be expanded upon, these data implicate generation of a C3 fragment by AP turnover as being responsible for releasing properdin into the circulation, and they represent an instructive example whereby a potent recognition and effector pathway maintains homeostasis of one of its components. The data also raise several interesting questions, including the nature of process by which a C3 fragment mediates properdin release and the physiologic reason behind such a mechanism to maintain properdin in plasma.

The mechanism whereby C3 turnover leads to properdin's presence in the circulation remains to be solved. We considered several possibilities as these studies progressed. Our experiments make it unlikely that (i) a low-affinity interaction (2931) occurs with native C3, because properdin is reduced in fB- and fD-deficient mice that have normal C3 levels (it remains a possibility though that continuous, low-level production of C3b or C3(H2O) by the AP is necessary to restrict properdin to the intravascular space) or (ii) C3a and/or C5a interact with their respective receptors on myeloid cells to release properdin from these cells. This possibility was a particularly attractive consideration because properdin is stored in the secondary granules of neutrophils where it is released upon cell activation (24). However, C5-deficient mice have normal blood properdin levels, as do C3aR−/−, C5aR−/−, and C3aR−/−C5aR−/− mice. Other C3 fragments, such as iC3b or C3dg, could be responsible. Mice lacking CR1 and CR2 have normal properdin levels in blood, but we have not tested CR3- and CR4-deficient mice. An intriguing possibility is C3f. This α-chain fragment originates from the limited proteolytic cleavage by complement regulatory proteins to generate a 17-aa peptide that was originally named neutrophil releasing factor (37). In these early experiments, mice were injected with purified C3f and their neutrophil counts increased (37). Concerns relative to contamination with endotoxin, anaphylatoxins, and various lymphokines and cytokines have been raised. This C3f fragment has recently received more attention as a marker of complement activation in proteomic analyses of peripheral blood proteins in several human diseases (38). In summary, we plan to focus ongoing investigations on three possibilities: namely, properdin interactions with C3b, C3(H2O), or iC3b; properdin release via engagement of CR3 or CR4 by iC3b; and properdin mobilization by C3f.

A second question raised by these studies relates to why the baseline concentration of properdin in the circulation is relatively low and requires AP turnover of C3 to maintain even this amount. Our working hypothesis is that low concentrations in plasma are desirable, preventing excessive intravascular complement activation. Physiologic turnover of AP occurs continuously, both in the fluid phase and on cells, as demonstrated by fH−/− and Crry SKO mice, respectively (16, 18). Amplification of the feedback loop is perhaps not required (or desirable) for routine tickover or the daily clearance of debris. Instead, in these two scenarios, the goal may be more one of limited and restricted activation of the complement cascade (39). Stabilization of the AP pathway on altered self or enhanced nonspecific turnover is generally to be avoided. However, there must be sufficient properdin in blood to allow the complement system to efficiently protect against intravascular invasion by bacteria, the major group of pathogens for which AP provides host defense. Thus, the invading bacterial pathogen can be exposed to optimal complement activation to destroy the organism. However, excessive intravascular complement activation is undesirable and part of the septic shock syndrome to which C3a and C5a contribute (40). Instead, the system seems to be designed to prevent excessive intravascular complement activation by, for example, rapidly consuming the limited quantity of properdin. In contrast, at extravascular inflammatory sites, neutrophils discharge their granules containing properdin to enhance complement activation.

Predictions that we would make based on these ideas include the following: (i) properdin is not required for the continuous low level AP tickover/turnover; (ii) properdin plays a modest role in the routine, daily clearance of cellular debris; (iii) properdin levels in the circulation increase minimally or not at all in most infectious states (properdin is not part of the acute phase response or synthesized by hepatocytes); instead, its concentration increases locally at the site of infection secondary to the presence of infiltrating leukocytes carrying properdin, leading to robust AP activation in the infectious microenvironment; and (iv) properdin isolated by column chromatographic methodology has several properties distinct from properdin in plasma (2, 41) that may mimic characteristics acquired by properdin at an inflammatory site. We conclude that properdin homeostasis is designed to provide limited properdin in the plasma compartment but larger quantities at the infectious site through release by infiltrating leukocytes.



Crry heterozygous (Crry+/−) and Crry single-knockout (Crry SKO) were backcrossed to the B6 background for 10 generations as described previously (27, 28). The origins of the complement-deficient mice were as follows: C3−/− (42), C4−/− (43), fB−/− (33), fD−/− (34), C1q−/− (44), CD55−/− (45), and Cr2−/− (46). B10.C5−/− and B10 WT mice were purchased from the Jackson Laboratory. Experiments were conducted under approved protocols of the Animal Studies Committee of Washington University School of Medicine.

Immunoprecipitation and Western Blotting for Properdin.

Due to the low concentration of properdin in blood, a pull-down assay followed by Western blotting was developed. Mouse serum (up to 200 μL) was incubated with 2 μL of goat anti-human properdin antibody (Complement Tech) for 3 h at 4 °C and then overnight at 4 °C with 25 μL of a 50/50 slurry of washed Protein A-conjugated Sepharose 4B beads (Invitrogen). After washing three times with PBS, SDS-reducing buffer solution was added to elute properdin from the pelleted beads. The eluate, usually equivalent to properdin in 100 μL of serum, was analyzed by SDS/PAGE under reducing conditions, followed by Western blotting. The secondary antibody was an HRP-conjugated rabbit anti-goat reagent (Sigma-Aldrich). After three washes, the nitrocellulose membranes were developed with SuperSignal West Kit (Thermo Scientific). In the initial experiments using WT, Crry+/−, and Crry SKO mice, the quantity of properdin detected by Western blotting was linear over a range of 25–100 μL of serum. Western blots to assess C3, fB, and fH were performed as described (18). Serum samples from C5aR−/−, C3aR−/−, and C3aR−/−C5aR−/− mice were supplied by Jackson Labs, Scott Drouin (University of Texas, Houston), and Craig Gerard (Children’s Hospital, Boston), respectively.

Serum and Bone Marrow Transfer Experiments.

To address properdin homeostasis in vivo, WT serum was transferred to Crry- or C3-deficient recipients. Wild-type serum (200 μL) was injected i.v. into Crry SKO or C3−/− mice. After transfer, serum was harvested to analyze properdin and C3. To assess the role of bone marrow-derived cells in maintaining serum properdin, C3−/− mice were irradiated with 1,000 rads and then reconstituted on the same day with WT bone marrow. WT bone marrow engraftment was assessed 8 wk later in the C3−/− hosts by analysis of C3 alleles in the peripheral blood leukocyte population.

Immune Complex Infusion and Localization.

Preformed immune complexes (peroxidase-rabbit anti-peroxidase; PAP) were used to activate the complement cascade (35). PAP (200 μg) were injected i.v. into WT and fB−/− mice, and blood was harvested at the time points indicated. Properdin was then measured as described above. To analyze IC deposition, the spleen was harvested 30 min following IC injection and snap-frozen using liquid nitrogen in OCT compound. Tissue sections (7 μm) were prepared. FITC-conjugated goat anti-rabbit IgG (Sigma–Aldrich) was applied to identify the IC. Rat anti-mouse Moma-1(Serotec) antibody followed by PE-conjugated anti-rat antibody (Vector Labs) was used to identify splenic marginal zone macrophages. PE-B220 (BD Biosciences) antibody was used to identify splenic marginal zone B cells.

Supplementary Material

Supporting Information:


We thank Kathy Liszewski and Dennis Hourcade for a critical review of the report; Lorraine Schwartz and Madonna Bogacki for assistance with manuscript preparation; Scott Drouin (University of Texas, Houston) for the C3aR−/− sera; Bao Lu and Craig Gerard (Children’s Hospital, Boston) for the C3aR−/−C5aR−/− sera; and Jessie Zhang for assistance with irradiation. This work was supported by National Institutes of Health Grants AI037618 and AI041592.


The authors declare no conflict of interest.

*This Direct Submission article had a prearranged editor.

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1006608107/-/DCSupplemental.


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