Disease severity in K/BxN serum transfer-induced arthritis is not affected by IL-33 deficiency
© Martin et al.; licensee BioMed Central Ltd. 2013
Received: 9 August 2012
Accepted: 8 January 2013
Published: 16 January 2013
Interleukin (IL)-33 is a cytokine of the IL-1 family, which signals through the ST2 receptor. Previous work suggested implication of the IL-33/ST2 axis in the pathogenesis of human and mouse arthritis. Here, we directly investigated the role of endogenous IL-33 in K/BxN serum transfer-induced arthritis by using IL-33 knockout (KO) mice.
Arthritis was induced by injection of complete K/BxN serum or purified IgG. Disease severity was monitored by clinical and histological scoring.
K/BxN serum transfer induced pronounced arthritis with similar incidence and severity in IL-33 KO and wild-type (WT) mice. In contrast, disease development was significantly reduced in ST2 KO mice. IL-33 expression in synovial tissue was comparable in arthritic WT and ST2 KO mice, and absent in IL-33 KO mice. Transfer of purified arthritogenic IgG instead of complete K/BxN serum also resulted in similar arthritis severity in IL-33 KO and WT mice, excluding a contribution of IL-33 contained in the serum of donor mice to explain this result. We investigated additional potential confounding factors, including purity of genetic background, but the mechanisms underlying reduced arthritis in ST2 KO mice remained unclear.
The data obtained with IL-33 KO mice indicate that endogenous IL-33 is not required for the development of joint inflammation in K/BxN serum transfer-induced arthritis. On the contrary, arthritis severity was reduced in ST2 KO mice. This observation might relate to IL-33 independent effects of ST2, and/or reveal the existence of confounding variables affecting the severity of joint inflammation in these KO strains.
Interleukin (IL)-33 is the most recently discovered member of the IL-1 cytokine family (see  for review). IL-33, like IL-1α, is a dual-function protein, displaying both nuclear and extracellular effects. The latter are mediated by its binding to an IL-1 receptor family member called ST2 (IL1RL1). ST2 exists in two isoforms generated by alternative splicing . The short isoform (sST2) acts as a soluble decoy receptor . The long signaling ST2 receptor isoform (ST2l) is expressed in many hematopoietic cells, including a number of innate immune cells, which are involved in T helper 2 (Th2)-type response. Consistently, injection of recombinant IL-33 induces or amplifies type 2 immune effects in different mouse models [4–6]. In addition IL-33 acts on neutrophils, Th1 cells, natural killer cells, and mast cells, as well as on endothelial cells, to induce proinflammatory effects, so that a role for IL-33 in host defense and immunopathology independently of Th2 immunity has also been suggested [7–9]. IL-33 is constitutively expressed in stromal cells, including epithelial cells and specialized fibroblasts, as well as in endothelial cells in human, but only to a limited extent in mouse [10, 11]. It has been proposed that, upon tissue damage, constitutively expressed IL-33 leaks from necrotic cells and acts as an alarmin to initiate or amplify immune responses [10, 12].
Previous work suggested a functional role of the IL-33/ST2 axis in the pathogenesis of human and mouse arthritis. In human rheumatoid arthritis (RA), IL-33 levels in serum and synovial fluid are elevated [13–15] and strong IL-33 expression can be detected in endothelial cells and fibroblasts in human RA synovium [16, 17]. In mouse models of experimental arthritis involving active immunization, such as collagen- and antigen-induced arthritis, the use of ST2 knockout (KO) mice, ST2 blockade or injection of sST2 led to decreased immune responses and severity of arthritis, while injection of recombinant IL-33 increased arthritis severity, suggesting a pathogenic role for IL-33, signaling through ST2, in these experimental models [18–21]. Two studies investigated involvement of IL-33 in the inflammatory effector phase of arthritis, as it can be studied in the K/BxN serum transfer-induced model [22, 23]. The first study concluded to a pathogenic role of IL-33 based on reduced arthritis severity in ST2 KO mice and increased disease severity after injection of IL-33 . The second study reported an opposite effect of IL-33 injection, which suppressed joint inflammation by enhancing the production of Th2 cytokines and upregulating the inhibitory Fc receptor FcγRIIB on macrophages .
In the present study, we directly investigated the role of endogenous IL-33 in K/BxN serum transfer-induced arthritis using IL-33 KO mice and compared the results to those obtained using ST2 KO mice. We confirm decreased severity of arthritis in ST2 KO, but not in IL-33 KO mice, suggesting that endogenous IL-33, although expressed in the synovium, is not required for the development of arthritis in this model.
Materials and methods
C57BL/6 mice were obtained from Janvier (Le Genest-St-Isle, France). IL-33 KO mice (B6.129Sv-Il33) were generated at Amgen Inc. (Thousand Oaks, CA, USA) by targeting of the Il33 gene in 129Sv ES cells resulting in the deletion of six out of the seven coding exons . Genotyping was performed by a 3-primer PCR combining a common forward primer (5'-TGC TGA ATT TTA TTC TCC CCC C-3') with reverse primers specific for the wild-type (WT) (5'-GCC CGT CTT CAT GTT GAA ATA-3') or the KO (5'-GCT CAT TCC TCC CAC TCA TGA-3') allele. IL-33 KO mice were backcrossed to the C57BL/6 background for six generations by speed congenics and considered to be 100% congenic based on analysis of a 377 SNIP panel (Taconic, Hudson, NY, USA). ST2 KO C57BL/6 mice (Il1rl1tm1Anjm, ) were obtained from the MRC Laboratory of Molecular Biology (Cambridge, UK). For arthritis experiments, local colonies of WT, IL-33 KO and ST2 KO mice were established at the Centre Médical Universitaire in Geneva. KRN T cell receptor transgenic mice  were provided by the Institut de Génétique et de Biologie Moléculaire et Cellulaire (Strasbourg, France) and maintained on a C57BL/6 background (K/B). NOD/Lt mice were purchased from Charles River (L'Arbresle, France). Mice were housed under conventional or low barrier conditions. Institutional approval was obtained for all animal experiments (Geneva Veterinarian Office, licenses 31.1.1005/3402/2, 3402/2-C and 3402/2-R).
Blocking anti-ST2, anti-IL-1RI and isotype-matched control antibodies were generated at Amgen Inc. Cell culture media were obtained from Invitrogen Life Technologies (Basel, Switzerland). Recombinant mouse IL-33 was purchased from Enzo Life Sciences (Lausen, Switzerland), human IL-1β and mouse IL-18 from R&D Systems (Abingdon, UK), and purified lipopolysaccharide (LPS) from Fluka (Escherichia coli 055:B5, Buchs, Switzerland). Murine IL-36β was produced at Amgen Inc. as an N-terminal truncation variant .
K/BxN serum transfer-induced arthritis
Arthritic K/BxN mice were generated by crossing K/B mice with NOD/Lt mice, adult arthritic K/BxN mice were bled, and the sera were pooled. Age-matched female recipient WT, IL-33 KO or ST2 KO C57BL/6 mice were injected with pooled serum (200 μl, i.p.) on days 0 and 2. Alternatively, WT C57BL/6 mice were injected with pooled serum (200 μl, i.p.) on days 0 and 2, as well as with a monoclonal murinized immunoglobulin G (IgG1)-blocking anti-ST2 antibody (150 μg/mouse), a monoclonal murinized IgG1-blocking anti-IL-1R1 antibody (150 μg/mouse), or a monoclonal mouse IgG1 antibody directed against an irrelevant human antigen that was used as an isoytpe-matched control antibody (150 μg/mouse), on day 0 (4 h before injection of K/BxN serum) and on day 3 (experiment 1), or on days 0 and 2 (4 h before each injection of K/BxN serum; experiment 2). Efficacy of the blocking anti-ST2 antibody was demonstrated previously [24, 28]. The development of arthritis was assessed daily and the severity of arthritis was scored in a blinded fashion for each paw on a 3-point scale, in which 0 = normal appearance, 1 = localized edema/erythema over one surface of the paw, 2 = edema/erythema involving more than one surface of the paw, 3 = marked edema/erythema involving the whole paw. The scores of all four paws were added for a composite score. Mice were sacrificed on day 6.
Purification of the total IgG fraction from K/BxN serum and induction of arthritis
Serum of arthritic K/BxN mice (20 ml) was purified on protein A/G Sepharose 4 Fast Flow (GE Healthcare Life Sciences, Glattbrugg, Switzerland) and dialyzed into PBS . Recipient WT, IL-33 KO or ST2 KO mice were injected with the purified IgG fraction (450 μl i.p., corresponding to 200 μl of the initial volume of K/BxN serum) on days 0 and 2. Mice were assessed for arthritis severity daily and sacrificed on day 6.
Histological grading of arthritis
At sacrifice, the right ankle joints were fixed in 10% buffered formalin, decalcified in 15% EDTA, and embedded in paraffin. Sections were stained with hematoxilin and eosin or toluidine blue and graded by one pathologist (CAS) in a blinded manner. The severity of the synovial inflammation including synovial hyperlasia and the % of polymorphonulcear (PMN) cell infiltration, as well as the degree of cartilage erosion and bone destruction were evaluated utilizing a scoring system ranging from 0 to 4 (0 = normal, 1 = minimal, 2 = moderate, 3 = severe, 4 = very severe) .
Primer sequences for RT-qPCR analysis.
Determination of cytokine levels in serum and tissue lysates
Serum and right wrist joints were harvested at sacrifice. Joints were homogenized in 500 μl of lysis buffer (50 mM Tris-HCl, pH 7.5, 150 mM NaCl, complete EDTA-free protease inhibitor cocktail (Roche Diagnostics AG, Rotkreuz, Switzerland)). Lysates were cleared by centrifugation and total protein content was determined with the DC protein assay kit (Bio-Rad Laboratories Inc.). IL-33 was quantified using a mouse IL-33 Milliplex cytokine magnetic beads assay (Millipore AG, Zug, Switzerland; detection limit 1.61 and 4.3 pg/ml in two different kits used). IL-6 levels were quantified using a DuoSet ELISA Development System (R&D Systems; detection limit 16 pg/ml).
IL-33 protein expression was examined in knee joints of WT and ST2 KO mice using a polyclonal goat anti-IL-33 antibody (AF3626, R&D Systems). Formalin-fixed, decalcified, paraffin-embedded sections were deparaffinized and antigen retrieval was performed in a pressure chamber (Pascal; Dako, Baar, Switzerland) in 0.1 M Tris-HCl, pH 9.0, 0.01 M EDTA, at 125°C for 30 sec. Slides were blocked for endogenous peroxidase activity and incubated with anti-IL-33 antibody (1 μg/ml) in antibody diluent (number S2022, Dako) overnight at 4°C. Subsequently, slides were incubated with an anti-goat HRP antibody (1:500; number SC2304, Santa Cruz Biotechnology, Inc., Heidelberg, Germany) in antibody diluent and developed with diaminobenzidine (Dako). To assess staining specificity, negative controls were performed using knee sections of IL-33 KO mice.
Bone marrow-derived dendritic cells (BMDC) were generated from WT, IL-33 KO and ST2 KO C57BL/6 mice as previously described . On day 7, cells were seeded into triplicate wells of 96-well plates at 105 cells/ml and cultured without or with 100 ng/ml recombinant IL-33, IL-1β, IL-36β or IL-18 or LPS for 72 h. IL-6 production in culture supernatants was assessed by ELISA. Cells from triplicate wells were pooled and used for total RNA extraction using the RNeasy kit (Qiagen, Valencia, CA, USA). Expression of IL-1R family receptors was quantified by RT-qPCR using appropriate sets of primers (Table 1).
Microsatellite marker genotyping
To assess differences in the longitudinal evolution of arthritis outcomes, we used generalized linear mixed models for repeated measures . Tests were conducted at error alpha level of 0.05, two-sided and performed with STATA v. 11 for Windows (StataCorp LP, College Station, TX, USA). Differences in arthritis severity at the end of the follow-up were evaluated using the Kruskal-Wallis test. Significance of differences in histological scores, cytokine measurements, and mRNA expression was assessed by ANOVA or Kruskal-Wallis test, as appropriate.
IL-33 and ST2 KO mice display different phenotypes in K/BxN serum transfer-induced arthritis
We examined incidence and severity of K/BxN serum transfer-induced arthritis in IL-33 KO, ST2 KO and WT C57BL/6 mice. Clinical scoring showed reduced incidence and severity of arthritis in ST2 KO mice as compared to WT controls (Figure 1A-C). In contrast, arthritis development and severity in IL-33 KO mice was similar to the disease observed in WT mice. Histological scoring of arthritic ankles on day 6 confirmed a trend toward reduced inflammation and PMN cell infiltration, as well as reduced cartilage and bone erosion in ST2 KO paws (Figure 1D).
IL-33 and ST2 KO mice display different phenotypes in arthritis induced by injection of arthritogenic IgG
Inhibition of ST2 signaling with a blocking antibody does not reduce K/BxN serum transfer-induced arthritis
Expression and function of other IL-1R family members in IL-33 and ST2 KO mice
Influence of genetic background on arthritis severity in ST2 KO mice
Primer sequences for chromosome 1 microsatellite analysis.
Our results indicate that, although IL-33 is expressed in the synovium during K/BxN serum transfer-induced arthritis, IL-33 KO mice display similar arthritis severity as compared to WT controls, suggesting that endogenous IL-33 is not required for the development of joint inflammation in this experimental model. Contrastingly, disease severity was reduced in ST2 KO mice.
We thus confirm previous data indicating that ST2-deficient mice have reduced severity of serum transfer-induced arthritis . However, this effect seems unrelated to the role of endogenous IL-33 and we have not been able to determine precisely why ST2 KO display less severe arthritis. The reduction of joint inflammation in ST2 KO mice is consistent in our hands and in experiments performed by others  and this observation certainly merits further investigation. Interestingly, we observed not only reduced inflammation, but also reduced bone erosion in ST2 KO mice. This finding is different from data reported previously [40, 41], describing a deleterious effect of the ST2 KO on bone, at steady state and in the context of TNF-α-induced arthritis. In contrast, in the present highly inflammatory model of arthritis, bone loss appeared to correlate mostly with the degree of inflammation, rather than being associated with a particular genotype.
In the course of these experiments, we observed nuclear expression of the IL-33 protein in the arthritic synovium. However, in striking contrast with human synovium  and consistent with data in other mouse tissues , IL-33 expression was not detected in endothelial cells in arthritic mouse paws. This observation emphasizes important differences in IL-33 biology between human and mouse, which need to be taken into account when inferring IL-33 function in human physiology or pathology from mouse data.
Discrepant observations in studies using different ST2 KO lines, or even in different studies using the same mouse line, as well as between ST2 KO and IL-33 KO mice, have already been reported in other models, and in particular in the context of allergic airway inflammation [42–45]. However, this study is, to our knowledge, the first instance where IL-33 and ST2 KO mice are compared side by side in the same experiment. Our observation that endogenous IL-33 is not required for the development of joint inflammation in serum transfer-induced arthritis differs from previous conclusions based on indirect evidence obtained using ST2 KO mice and injections of recombinant IL-33 [22, 23], suggesting that caution is warranted when extrapolating such data to conclude on functions of endogenous IL-33, as already highlighted by other studies [46–48].
We considered a number of potential confounding variables to explain our discrepant observations in IL-33 and ST2 KO mice. Among these, we excluded contamination of injected serum with IL-33 to explain the lack of difference between IL-33 KO and WT mice. We also analyzed the potential interference of ST2 gene targeting with expression of other IL-1R family receptors encoded in the same gene cluster on mouse chromosome 1. Using BMDC isolated from WT, IL-33 KO or ST2 KO mice, we found no evidence for a major defect in expression or function of one of these receptors in ST2 KO cells. However, based on our limited set of data, we cannot exclude more subtle alterations in gene expression or signaling that might affect arthritis severity. Furthermore, we serendipitously observed that, although ST2 KO cells lack surface expression of ST2l ( and our unpublished observations), and display no functional response to IL-33 , the 3' part of the ST2l mRNA is still expressed in ST2 KO cells and tissues, to levels similar to those detected in WT mice (PM et al., unpublished observations). By 5'RACE, we localized the 5' end of the truncated ST2l transcript in ST2 KO cells to exon 8 of the ST2 gene (bp 1081 of the ST2l cDNA, GenBank accession NM_001025602). This transcript includes an open reading frame potentially encoding a truncated ST2l protein starting at amino acid 346, which corresponds to the beginning of the intracellular domain of the receptor. Although, due to lack of a suitable antibody recognizing the intracellular part of mouse ST2l, we have not been able to verify expression of a truncated protein in ST2 KO mice, expression of a free ST2 Toll/IL-1R (TIR) domain might conceivably interfere with signaling of other IL-1R family receptors, by analogy to regulation of IL-1R and Toll-like receptor (TLR) signaling by the IL-1R family member SIGIRR . Interestingly, and whatever the mechanism involved, there is previous evidence for complex alterations in the response to another IL-1 cytokine in ST2 KO cells, with basophils of ST2 KO mice showing decreased responses to IL-18 in terms of IL-4 and IL-13, but not IL-6, production, as compared to WT cells .
We also considered the potential existence of microRNAs (miRNAs) within and around the ST2 locus, the expression of which might have been affected by ST2 targeting. To date, by searching miRBase , we found no miRNA described in proximity of the Il1rl1 gene (chromosome 1; 40.5 Mb), the closest miRNAs reported being mmu-mir-5103 (miRBase accession number MI0018011; 34.5 Mb) and mmu-mir-1928 (MI0009917; 74.3 Mb).
A previous study described higher severity of K/BxN serum transfer-induced arthritis in C57BL/6, as compared to 129 WT mice , and we wondered whether carryover of genetic material from the original 129 strains might have affected arthritis severity in the IL-33 and ST2 lines used in this study. While IL-33 KO mice were backcrossed to high purity to C57BL/6, the backcross was less complete in ST2 KO mice, and we observed persistence of non-C57BL/6 markers on chromosome 1, close to the ST2 locus, but also on chromosomes 6, 11 and 15. However, in the regions examined, arthritis severity often tended to be even less severe in the few mice, which carried two C57BL/6 alleles, so that we cannot provide evidence for any obvious effect of 129 carryover in decreasing joint inflammation. Nevertheless, more complex genetic interactions among multiple chromosomal sites acting to affect disease severity in these mice cannot be excluded based on this limited analysis.
Obviously, an alternative explanation for the difference in arthritis severity observed between ST2 and IL-33 KO mice might lie with the existence of another ligand for ST2, although we are not aware of data designating a candidate molecule for this function and we have been unable to demonstrate any substantial binding interaction between ST2 and any other IL-1 family member besides IL-33. In an attempt to determine whether reduced arthritis severity in ST2 KO mice might relate to a true IL-33 independent effect of ST2, we used blocking anti-ST2 antibodies to inhibit ST2 signaling during K/BxN serum transfer-induced arthritis. In these experiments, treatment of the mice with anti-ST2 antibodies did not reduce disease severity, while blocking of the type 1 IL-1R with an isotype-matched anti-IL-1R1 blocking antibody essentially abrogated disease. This observation suggests a minor contribution, if any, of ST2 signaling to disease severity, as opposed to a major contribution of IL-1R1, consistent with the previously reported critical role of IL-1 in arthritis pathogenesis in this model . The anti-ST2 antibody used efficiently prevented the biological activity of recombinant IL-33 in vitro and injected in vivo [24, 28]. However, it is unknown whether the IL-33 blocking ability of this antibody would translate into the blocking of an IL-33-independent activity. Furthermore, although suggested by the efficacy of the anti-IL-1R1 antibody, complete target coverage of the antibody within the joint over the whole duration of the arthritis experiment seems difficult to verify. Therefore, although we consider it unlikely, we cannot formally exclude a marginal role of ST2 signaling in the pathogenesis of K/BxN serum transfer-induced arthritis.
In contrast to our present observations, we previously reported that treatment with a blocking anti-ST2 antibody efficiently reduced disease severity in collagen-induced arthritis, [18–21]. In fact, in mouse models of arthritis involving active immunization, such as collagen- or antigen-induced arthritis, the use of ST2 KO mice, injection of anti-ST2 antibodies or treatment with sST2 consistently led to decreased immune responses and severity of arthritis [18–21]. Conversely, injection of recombinant IL-33 enhanced disease severity, suggesting a role for IL-33, signaling through ST2, in modulating the pathogenic adaptive immune responses in these models. Nevertheless, in the light of our present work, it needs to be stressed that the contribution of endogenous IL-33 has not been directly investigated in this context and remains to be formally demonstrated.
These data indicate that, while IL-33 is expressed in the synovium during K/BxN serum transfer-induced arthritis, IL-33 KO mice displayed similar arthritis development and severity as WT controls. Contrastingly, disease severity was reduced in ST2 KO mice; however, genetic analysis revealed that the degree of backcrossing in ST2 KO mice is much less complete. It is unclear, therefore, whether the difference between IL-33 and ST2 KO mice relates to IL-33 independent effects of ST2 or, instead, the existence of confounding variables affecting the severity of joint inflammation in these KO strains.
bone marrow-derived dendritic cell
enzyme-linked immunosorbent assay
quantitative reverse transcription-polymerase chain reaction
tumor necrosis factor alpha
We would like to thank Deborah Strebel and Vanessa Bochet for their expert technical assistance, Shozo Izui, Guy Brighouse, and Philippe Hammel for their help with IgG purification, Laurence Chatel for her help with the Milliplex analysis and Daniel Pinschewer for helpful discussions. This work was supported by grants from the Swiss National Science Foundation (310030-135195 to CG and 310030-134691 to GP), the Rheumasearch Foundation, the Institute for Arthritis Research, and the de Reuter Foundation.
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