Mechanisms of complement activation by dextran-coated superparamagnetic iron oxide (SPIO) nanoworms in mouse versus human serum
© Banda et al.; licensee BioMed Central Ltd. 2014
Received: 30 May 2014
Accepted: 8 November 2014
Published: 26 November 2014
The complement system is a key component of innate immunity implicated in the neutralization and clearance of invading pathogens. Dextran coated superparamagnetic iron oxide (SPIO) nanoparticle is a promising magnetic resonance imaging (MRI) contrast agent. However, dextran SPIO has been associated with significant number of complement-related side effects in patients and some agents have been discontinued from clinical use (e.g., Feridex™). In order to improve the safety of these materials, the mechanisms of complement activation by dextran-coated SPIO and the differences between mice and humans need to be fully understood.
20 kDa dextran coated SPIO nanoworms (SPIO NW) were synthesized using Molday precipitation procedure. In vitro measurements of C3 deposition on SPIO NW using sera genetically deficient for various components of the classical pathway (CP), lectin pathway (LP) or alternative pathway (AP) components were used to study mechanisms of mouse complement activation. In vitro measurements of fluid phase markers of complement activation C4d and Bb and the terminal pathway marker SC5b-C9 in normal and genetically deficient sera were used to study the mechanisms of human complement activation. Mouse data were analyzed by non-paired t-test, human data were analyzed by ANOVA followed by multiple comparisons with Student-Newman-Keuls test.
In mouse sera, SPIO NW triggered the complement activation via the LP, whereas the AP contributes via the amplification loop. No involvement of the CP was observed. In human sera the LP together with the direct enhancement of the AP turnover was responsible for the complement activation. In two samples out of six healthy donors there was also a binding of anti-dextran antibodies and C1q, suggesting activation via the CP, but that did not affect the total level of C3 deposition on the particles.
There were important differences and similarities in the complement activation by SPIO NW in mouse versus human sera. Understanding the mechanisms of immune recognition of nanoparticles in mouse and human systems has important preclinical and clinical implications and could help design more efficient and safe nano-formulations.
Superparamagnetic iron oxide (SPIO) is one of the most widely cited metal oxide nanoparticle that has been used as magnetic resonance imaging (MRI) contrast agent alone and as a component of multifunctional nanomedicines . Dextran SPIO consists of magnetite-maghemite (Fe3O4 and γ-Fe2O3) crystalline cores of 3–10 nm size coated with dextran or carboxymethyl dextran . Despite the tremendous medical need in efficient MRI contrast agents , several dextran SPIO formulations have been withdrawn from the clinical use due to hypersensitivity in patients (Sinerem, Combidex, Feridex). Another problem of these nanomaterials is the propensity of dextran SPIO for liver and spleen clearance, which limits imaging to macrophage-rich organs. In order to design contrast agents with reduced toxicity and improved pharmacokinetics, a basic understanding of immune recognition of these materials in both mouse (preclinical) and human (clinical) systems of paramount importance.
The complement system accounts for about 5% of globulins in serum and is responsible for recognition, elimination and destruction of pathogens . Activation of the complement on the foreign surface takes place via either the classical pathway (CP), the lectin pathway (LP) or the alternative pathway (AP). The CP activation is triggered via initial binding of IgG or IgM to the pathogen surface, followed by binding and activation of C1q component and formation of C4bC2a, a C3 convertase. C4bC2a cleaves C3 into C3a and C3b, and the latter covalently attaches via highly reactive thioester group to hydroxyls and amines on the foreign surface . More C3b is formed through the alternative pathway (AP) via the formation of alternative C3 convertase C3bBb. Lectin pathway (LP) is somewhat different in mice vs. humans. In mice, the activation is primarily triggered via initial binding of mannose-binding lectin -A and -C or ficolin A to carbohydrates on the pathogen surface, leading to activation of MBL-associated serum protease MASP-2 and formation of C4bC2a, the C3 convertase. In humans, five different sugar recognition molecules have been identified that are able to initiate the LP: MBL, M-, L-, and H-ficolins; and collectin 11 (CL11 or CL-K1), but the downstream activation of the classical C3 convertase is believed to be similar in mice and humans .
Activation of the complement plays a major role in the immune recognition of nanoparticles and pathogens . Opsonization by C3b and its cleavage products (e.g., iC3b) triggers recognition by complement receptors CR3 (also known as CD11b/CD18 or Mac-1), complement receptor CR4 (CD11c/CD18), and complement receptor immunoglobulin (CRIg) ,, leading to particle uptake by macrophages. Complement cleavage byproducts C3a and C5a are among the most potent anaphylatoxins and proinflammatory molecules with low nanomolar affinity . Many nanoparticulate systems including iron oxides exhibit signs of the complement activation in vivo-. At the same time, despite the accumulating evidence on the involvement of complement in acute and often life threatening reactions observed in some patients infused with dextran SPIO, the mechanisms of complement activation are not clear. Our earlier report using shotgun proteomics demonstrated the absorption of the LP components MBL-A/C and MASP-1/2 from mouse plasma on the SPIO surface . The involvement of the LP in the complement activation would be a logical assumption, since dextran is a polysaccharide and as such may be recognizable via the LP . This contrasts the reported mechanisms of activation in human sera. Pedersen et al. demonstrated that iron oxide nanoparticles of large curvature activate the CP in human plasma  due to the presence of specific anti-dextran IgM antibodies in certain individuals. In view of the above-mentioned similarities and differences between mouse and human complement systems, we set out to systematically study the mechanisms and pathways of the complement activation in mouse versus human sera. For the study below we used our previously described 20 kDa dextran-coated SPIO nanoworms (SPIO NW) that have physicochemical and biological properties similar to Feridex ,. Our data suggest that SPIO NW activate complement in mouse and human sera, but the mechanisms of activation are different, which could bear important implications on preclinical and clinical studies of these materials.
Results and discussion
Mechanisms of complement activation by SPIO in mouse sera
In order to further investigate the pathways by which SPIO NW trigger mouse complement we examined C3 fragment deposition after incubation of SPIO NW with sera genetically lacking specific complement components. The serum was mixed with SPIO NW at a final iron concentration of 0.15 mg/ml and serum concentration of 75% v/v. There was a 97% decrease in C3 deposition in serum from wild type (WT) mice supplemented with 5 mM ethylenediamine tetraacetic acid (EDTA) (Figure 1e), since complement activation via all pathways requires both Ca2+ and Mg2+ ions. Also, there was not detectable C3 deposition in C3 −/− serum. Activation of the LP proceeds following the binding of serum MBL or the binding of serum Ficolin A (FcnA) to a LP-activating surface . There was 95% less C3 deposition in MBL-A/C −/− mouse serum compared to normal mouse serum (Figure 1e). There was a similar decrease in C3 deposition in the sera lacking both MBL-A/C and FcnA (MBL-A/C −/− FcnA −/− ), and no decrease in FcnA −/− serum (Figure 1e), confirming that complement activation in mouse serum depends on MBL-A/C and not on FcnA. Three different types of mannose-associated serine proteases (MASPs), i.e. MASP-1, MASP-2 and MASP-3 have been reported to be associated with MBL or ficolins in mouse sera ,. In order to confirm the role of the LP in the complement activation, we measured C3 deposition using mouse serum deficient for MASP-2. In MASP-2 −/− mouse serum there was a significant (p <0.05) 91% reduction in C3 deposition on the surface of SPIO NW (Figure 1e). At the same time, there was no significant decrease in C3 deposition in the C1q −/− serum (Figure 1e). C1q is required for the initiation of the CP of complement. There was nearly complete loss of C3 binding to SPIO NW in double knockout MBL-A/C −/− C1q −/− serum, but no decrease of C3 binding in C1q −/− serum compared to WT serum (Figure 1d), suggesting that the CP plays a minor, if any role, in mouse complement activation and C3 deposition. On the other hand, mannose, which is the inhibitor of the LP, decreased C3 deposition in a concentration-dependent fashion (Figure 1f). Combined, these experiments confirm the critical role of the LP in the complement activation on SPIO NW in mouse serum.
To determine the role of AP in the complement activation and C3 deposition, we used sera genetically deficient for critical components of the AP: factor D (FD) and factor B (FB). Following the initial deposition of C3b, the amplification via the AP takes place through the binding of FB to C3b, subsequent cleavage into Bb by FD and formation of C3bBb (alternative C3 convertase). According to Figure 1g, the deposition of C3 in FB −/− serum as well as in serum in which FB was immunochemically depleted with a previously validated antibody , was 90% less than that of WT serum. C3 deposition was also decreased by 92% in the FD −/− serum and by 82% in C1q −/− FD −/− serum. The higher deposition of C3 in the C1q −/− FD −/− serum compared to FD −/− serum is interesting and could suggest compensatory activity of the LP in the double negative sera. C3 deposition in double negative MBL-A/C −/− FD−/− − serum was decreased by 97% compared to WT serum and by 6% compared to FD −/− serum. Collectively, these experiments confirm that in mouse sera the complement activation is initiated mainly via the LP and amplified via the AP, and that the amplification loop adds the majority of C3 deposited on the surface of SPIO. There is a possibility that MBL-A/C and/or MASP-1/2 could directly trigger the activation of the AP, as was suggested previously ,, but we did not investigate this hypothesis further. Some level of the complement activation that is not inhibited in MBL A/C −/− FD −/− serum is probably due to a baseline spontaneous C3 hydrolysis and formation of C3H2O but we did not investigate this hypothesis further.
Mechanism of complement activation by SPIO NW in human serum
Albeit mouse and human complement systems share similarities, the relative contribution of pathways to the complement activation could be different . Therefore, we determined the contribution of each of the pathways using human serum. Since human sera deficient for the complement factors and components are not readily available, we used a previously established combination of depleted sera and purified complement factors . In addition, due to the availability of commercial quantitative assays, we measured fluid phase markers rather than the C3 deposition for measuring complement activation.
Major questions regarding the interaction between nanoparticle surface chemistry and the complement components still remain. Thus, MBLs bind to wide range of sugars, including mannose and glucose , and it is likely that lectins also bind to the dextran coat on SPIO, but at this point we did not investigate the exact mechanisms of assembly of the LP components on the nanoparticle surface. One interesting possibility could be that MBLs bind to serum protein corona, rather than through direct binding to the dextran chains. It is also not clear how dextran structure and molecular weight affect the assembly of the complement components, and whether the relative contribution of the pathways depends on the nanoparticle chemistry. Several studies failed to demonstrate a conclusive correlation between molecular weight of dextran and the complement activation by polymeric nanoparticles, with dextran conformation (“loops and trains” vs. “end-on”) postulated as being the most important factor in the activation efficiency ,. The role of nanoparticle surface properties in the complement activation needs to be rigorously addressed in future studies.
In conclusion, our results reveal important similarities and differences between preclinical (mouse) and clinical (human) systems with respect to complement activation by SPIO NW. It is plausible to suggest that the observed immunological behavior of SPIO NW could be applied to Feridex and other variants of dextran SPIO nanoparticles. Although Feridex and other dextran SPIO have been discontinued from the clinical use, the results of our study are critically important for development of new, more safe MRI contrast agents. In that regard, it is clear from our studies that strategies to reduce complement activation by nanoparticles in a mouse system might not necessarily translate into a human system. Mechanistic studies of nanoparticle immune recognition should become an integral part of nanomedicine research and development in order to advance nanomedicine to a new level.
Nanoparticle synthesis and characterization
SPIO NW was prepared by precipitation of Fe2+ and Fe3+ salts in ammonia in the presence of branched dextran of 20 kDa Mw (Sigma), as described elsewhere in the literature ,,. Particles were re-suspended in phosphate buffered saline (1xPBS) at 1–2 mg (Fe)/ml and filtered through a 0.2 μm membrane filter. Nanoparticle size (intensity distribution) was measured using a Zetasizer Nano (Malvern Instruments, Worcestershire, UK). For nanoparticle imaging with transmission electron microscopy, the nanoparticle solution in water was placed on Formvar-/carbon-coated grids (Ted Pella, Redding, CA, USA). After 5 min, the grid was gently blotted and air-dried. All the samples were studied without counterstaining. Grids were viewed using a JEOL 1200EX II transmission electron microscope at 75 kV and different instrumental magnifications. Images were captured using a Gatan digital camera.
Complement activation in mouse sera
In all these studies sera from WT or knock out mice on C57BL/6 J background were used. Mouse sera were collected as described  according to the protocols approved by the IACUC (Institutional Animal Care and Use Committee) and stored at or below −70°C before use. Each serum sample was subjected less than 2 freeze-thaw cycles, and aliquots were used whenever possible. C3 deposition on SPIO NW was determined by immunoblotting following incubation in normal sera or sera deficient for complement factors and components (obtained from the corresponding mice homozygous for the gene deficiencies ,,-). SPIO NW (final concentration 0.4 mg iron/ml in 1× PBS) was incubated with different dilutions of mouse sera (normally 10 μl particles and 30 μl serum) and incubated for 10–30 min at either room temperature of 37°C. Following incubation, the nanoparticles were washed with 1 ml PBS (without calcium or magnesium) four times by ultracentrifugation (Beckman TLA-100 ultracentrifuge, TLA-100.3 rotor, 55.000 rpm for 10 min) and resuspended in PBS at 0.5 mg/ml. As a washing quality control, a separate tube with serum but without nanoparticles was washed using the exact same procedure. Zymosan (2 × 109 particles/mL) was prepared by boiling 4 mg/mL solution of zymosan (Sigma Aldrich) in normal saline for 60 min, washing in PBS twice and resuspending in PBS + 0.1% sodium azide. For dot-blot assay, nanoparticles (1 μl, 0.5 μg iron) were spotted onto a 0.22 μm nitrocellulose membrane (Bio-Rad) in triplicates. The membrane was dried and blocked in 5% dry milk solution in Tween-20/PBS buffer. For western blotting, particles were boiled at 90°C for 5 min in the reducing sample buffer (Bio-Rad), loaded on a Tris-Glycine 4-20% minigel (Life Technologies), the proteins were separated and transferred to a nitrocellulose membrane using iBlot apparatus (Life Technologies). C3 on the membrane was detected with goat anti-mouse C3 polyclonal antibody (MP Biomedicals) and donkey anti-goat 800CW antibody (Li-COR Biosciences, Lincoln, NE). Membranes were scanned at 800 nm with Li-COR Odyssey scanner and the integrated C3 density of each dot was calculated with the NIH ImageJ software. The differences in the C3 deposition between sera were analyzed with non-paired two-sided t-test at 95% CI using Prism software (GraphPad, San Diego).
Complement activation in human sera
Human sera were either commercially obtained or collected according to the pre-approved IRB (Instutional Review Board) protocol. Details for preparation, characterization and functional assessments of complement pathways as well as determination of MBL and L-ficolin concentrations in normal human serum, C1q-depleted serum and MBL-deficient serum were in accordance with our previous studies ,,. MBL/MASP-2 preparation and characterization was described previously . To measure complement activation in vitro, we determined SPIO- and dextran-induced rise of serum complement activation products C4d, Bb and SC5b-9 using respective ELISA kits (Quidel, San Diego) according to the manufacturer’s protocols as described previously ,,,. For measurement of complement activation, the reaction was started by adding the required quantity of SPIO NW (or dextran) to undiluted serum in Eppendorf tubes (either in duplicate or triplicate, depending on experiment) in a shaking water bath at 37°C for 30 min, unless stated otherwise. Reactions were terminated by addition of ‘sample diluent’ provided with assay kits or saline containing 25 mM EDTA. Serum complement activation products were measured following nanoparticle removal by centrifugation. Control incubations contained saline (the same volume as SPIO) for background measurement of complement activation products. In some experiments, SPIO-mediated complement activation was monitored in the presence of EGTA/Mg2+ (10.0 mM/2.5 mM) as well as following restoration of serum with deficient complement protein. Zymosan (1 mg/mL) was used as a positive control for complement activation throughout. For quantification of complement activation products, standard curves were constructed using the assigned concentration of each respective standard supplied by manufacturer and validated as described earlier ,,,. The efficacy of SPIO NW (or dextran) treatments was established by comparison with baseline levels using paired t-test; correlations between two variables were analysed by linear regression, and differences between groups (when necessary) were examined using ANOVA followed by multiple comparison with Student-Newman-Keuls test.
Binding studies of anti-dextran antibody, C1q and C3 in human sera was performed on samples from non-smokers, age <35, males, white. Particles were incubated with sera, washed in PBS with 2 mM Ca2+/Mg2+ (for C1q) or in Ca2+/Mg2+ free PBS (for C3 and antibody), and immunoblotted as described above. Anti-dextran antibody was detected using IRDye 800CW (Li-COR) labeled anti-human antibody that is reactive with both IgG and IgM, C1q was probed with goat anti-human/mouse C1q (Santa Cruz Biotechnology) and then detected with donkey anti-goat IRDye 800CW, C3 was probed with goat anti-human C3 (MP Biomedicals) and detected with donkey anti-goat IRDye 800CW. Integrated density of the spots was calculated with ImageJ. For dextran inhibition studies, sera were preincubated with 10 mg/mL of 20 kDa dextran for 5 min prior to addition of nanoparticles. Correlation between C3 and C1q deposition was determined with Spearman two-tailed non-parametric test with 95% confidence interval.
This study was funded by the University of Colorado Denver startup funds to D.S. SMM acknowledges financial support by the Danish Agency for Science, Technology and Innovation (Det Strategiske Forskningsråd), reference 09–065746. Mouse anti-factor B antibody was provided to Dr. Banda for various collaborative studies by Dr. V. Michael Holers, UC Denver. MASP-1/3 −/− and MASP-2 −/− mice has been provided to Dr. Banda by Drs. Minoru Takahashi and Teizo Fujita, Fukushima Medical University, Japan. We would like to thank Dr. Robert Mattrey (University of California San Diego) for providing us with an aliquot of Feridex.
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