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Genetic Control Directed toward Spontaneous IFN-/IFN-β Responses and Downstream IFN- Expression Influences the Pathogenesis of a Murine Psoriasis-Like Skin Disease¹

Fuyuko Arakura^*,, Shigeaki Hida^*, Eri Ichikawa^*, Chihiro Yajima^*, Shinsuke Nakajima^*, Toshiaki Saida and Shinsuke Taki^2,*

^* Department of Immunology and Infectious Diseases, Graduate School of Medicine, Shinshu University, Matsumoto, Japan; and Department of Dermatology, School of Medicine, Shinshu University, Matsumoto, Japan

	Abstract

Top Abstract Introduction Materials and Methods Results Discussion Disclosures References

 
Psoriasis is an inflammatory skin disease, onset and severity of which are controlled by multiple genetic factors; aberrant expression of and responses to several cytokines including IFN-/IFN-β and IFN- are associated with this "type 1" disease. However, it remains unclear whether genetic regulation influences these cytokine-related abnormalities. Mice deficient for IFN regulatory factor-2 (IRF-2) on the C57BL/6 background (IRF-2^–/–BN mice) exhibited accelerated IFN-/IFN-β responses leading to a psoriasis-like skin inflammation. In this study, we found that this skin phenotype disappeared in IRF-2^–/– mice with the BALB/c or BALB/c x C57BL/6 F₁ backgrounds. Genome-wide scan revealed two major quantitative trait loci controlled the skin disease severity. Interestingly, these loci were different from that for the defect in CD4⁺ dendritic cells, another IFN-/IFN-β-dependent phenotype of the mice. Notably, IFN- expression as well as spontaneous IFN-/IFN-β responses were up-regulated several fold spontaneously in the skin in IRF-2^–/–BN mice but not in IRF-2^–/– mice with "resistant" backgrounds. The absence of such IFN- up-regulation in IRF-2^–/–BN mice lacking the IFN-/IFN-β receptor or β₂-microglobulin indicated that accelerated IFN-/IFN-β signals augmented IFN- expression by CD8⁺ T cells in the skin. IFN- indeed played pathogenic roles as skin inflammation was delayed and was much more infrequent when IRF-2^–/–BN mice lacked the IFN- receptor. Our current study thus revealed a novel genetic mechanism that kept the skin immune system under control and prevented skin inflammation through regulating the magnitude of IFN-/IFN-β responses and downstream IFN- production, independently of CD4⁺ dendritic cells.

	Introduction

Top Abstract Introduction Materials and Methods Results Discussion Disclosures References

 
As with most autoimmune diseases, the pathogenesis of autoimmune skin inflammation is complex, in which both environmental and genetic factors likely play important roles (1). A well-known example is psoriasis, a chronic immunological disorder of the skin in humans (2, 3). Several genome-wide scans have been conducted to reveal the polygenic nature of the disease as >10 susceptibility loci have been identified (4, 5). Among several other susceptibility loci, the PSORS3 locus is unique as it contains genes for immunoregulatory molecules such as IFN regulatory factor-2 (IRF-2)³ as well as IL-15, TLR2, and TLR3. IRF-2 was in fact reported as a candidate susceptible gene for psoriasis in Irish families (6), although examination in other families excluded variations in the IRF2 gene as a candidate of PSORS3 (7). These apparently contradicting observations may suggest that bias in concomitant variations of other genes might obscure the effect of IRF-2 polymorphism on susceptibility to psoriasis through epistasis.

As for the mechanism of inflammation in psoriasis, several cytokines have been suggested to play pathogenic roles, including IFN-/IFN-β, TNF-, IFN-, IL-12, IL-20, IL-22, and IL-23 (2, 8). Among these, the particularly important and longest known is IFN-/IFN-β. Thus, aberration of the IFN-/IFN-β system was reported in human psoriasis lesions (9, 10) and, accordingly, a gene expression profiling study showed that several IFN-inducible genes were up-regulated in psoriatic skin (11). More recently, IFN-/IFN-β produced by plasmacytoid dendritic cells (DCs) were shown to be essential to initiate psoriasis in a xenograft model (12). As a downstream event of IFN-/IFN-β, IFN- production by T cells was proposed to be critical for this cutaneous inflammation, exhibiting "type 1" characteristics (9, 13). However, despite the well-known association of IFN- expression and psoriasis, the roles of this cytokine in the pathogenesis are still to be directly demonstrated in patients and animal models (14, 15). Furthermore, studies on the genetic control of psoriasis have been focused almost exclusively on overall susceptibility, but not the pathogenic process itself, and how genetic elements influence the production of and responses to cytokines remains to be addressed.

IRF-2 is a transcription factor that functions as an attenuator of IFN-/IFN-β signaling as indicated by the up-regulated expression of IFN-inducible genes in IRF-2-deficient mice (IRF-2^–/– mice) (16). Such aberrant IFN-/IFN-β signals cause an inflammatory skin disease sharing several pathological alterations with human psoriasis with an autoimmune-like mechanism in which CD8⁺ T cells were essential (16). IRF-2^–/– mice have thus been regarded as one of the experimental supports for the involvement of IFN-/IFN-β in human psoriasis (4, 13, 17). Several immunological disorders have been described in IRF-2^–/– mice, such as impaired CD4⁺ myeloid DC development in the spleen and epidermis, defective NK cell maturation, uncontrolled basophil expansion, and reduced IL-12 production (18, 19, 20, 21, 22). Among those, only the CD4⁺ DC abnormality was shown to be dependent on IFN-/IFN-β signals (20) and could hence potentially take part in skin disease development by acting downstream of IFN-/IFN-β signals, a possibility reminiscent of the impaired function of myeloid DCs implicated in the pathogenesis of human psoriasis (23).

In this study, we found that IRF-2^–/– mice with the BALB/c background (IRF-2^–/–CN mice) did not develop the skin disease at all, in sharp contrast to those on the C57BL/6 background (IRF-2^–/–BN mice). Multiple quantitative trait loci (QTL) influenced the pathway leading to the severe skin disease in IRF-2^–/– mice, to which, however, the CD4⁺ DC-related phenotype was not integral. We also found that genetic elements derived from "resistant" BALB/c mice not only reduced spontaneous IFN-/IFN-β responses but also restored the elevated cutaneous expression of IFN- to the normal levels in IRF-2^–/– mice. Further genetic studies demonstrated that the up-regulation of IFN-, apparently derived from CD8⁺ T cells, was dependent on IFN-/IFN-β signals, and IFN- in fact played an important role in the progression of the skin disease. Our current study thus identified the uniqueness of IRF-2^–/– mice as an animal model for inflammatory skin disease with which otherwise hidden negative regulatory mechanisms were uncovered for spontaneous IFN-/IFN-β responses and downstream IFN- production. An important implication of this study would be that similar or related mechanisms might be involved in the genetic control of the susceptibility to human psoriasis, in which both IFN-/IFN-β and IFN- likely play critical pathogenic roles (13, 17).

	Materials and Methods

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Mice

IRF-2^–/– mice, originally generated from a 129/Ola strain-derived embryonic stem cells, were backcrossed at least 10 times to C57BL/6 mice (C57BL/6CrSlc; Japan SLC) (20). The same mice were independently backcrossed to BALB/c mice (BALB/cCrSlc; Japan SLC) >10 times (IRF-2^–/–CN mice). Female IRF-2^–/–CN mice were crossed with male IRF-2^–/–BN mice to generate IRF-2^–/–CBF1 hybrid mice. Furthermore, female IRF-2^–/–CBF1 mice were backcrossed to male IRF-2^–/–BN mice to generate backcrossed progeny for genome-wide screen, all of which carried the mutant IRF-2 locus on chromosome 8 (position 26 cM). Mice lacking the -chain of the receptors for IFN-/IFN-β or IFN- (IFNAR1^–/– and IFNGR1^–/– mice, respectively) were purchased from B&K Universal and those lacking RAG-1 or β₂-microglobulin (RAG^–/– and β₂m^–/– mice, respectively) were originally from The Jackson Laboratory. All of these mutant mice were backcrossed to C57BL/6 mice at least 10 times and then crossed to IRF-2^–/–BN mice to generate corresponding double mutants. Littermate mice heterozygous for the loci of interests were used for control, unless otherwise indicated. Mice were kept under specific pathogen-free conditions in the animal facility of Shinshu University. All animal experiments were approved by the Committee for Animal Experimentation of Shinshu University and conducted according to the guideline.

Evaluation of the skin disease

Backcrossed mice were scored for the skin disease macroscopically at 9–20 wk of age according to the criteria previously described (16). Formalin-fixed skin tissue were embedded in paraffin, sectioned, and stained with H&E as described (16). Cryosections of skin tissues were fixed in zinc fixative for IHC (BD Pharmingen) and cryosections were stained with monoclonal anti-F4/80 Ab (Caltag Laboratories) followed by biotin-anti-rat Ig (BD Pharmingen) and visualized with HRP-conjugated streptavidin (BD Pharmingen). Hematoxylin was used for counterstaining. Light microscopic pictures were taken with an AX-80 microscope (Olympus) equipped with the DP70 digital image capture system (Olympus).

Genotyping

Genomic DNA prepared from individual mice was genotyped for microsatellite markers that showed polymorphism between C57BL/6 and BALB/c mice using primer pairs, of which the sequences and genetic distances were taken from an online database (Mouse Genome Informatics; The Jackson Laboratory, www.informatics.jax.org). PCR primers for these markers were purchased from Qiagen and Greiner. In total, 47 pairs of primers were used for the initial analyses: for chromosome 1, four pairs of primers were used; three and two pairs of primers were used for chromosomes 2, 3, 4, 6, 10, 11 and 16 and for chromosomes 5, 7–9, 12–14, 15, 17–19, respectively. The average interval between the markers was 20–30 cM and several more markers were used where necessary. As for chromosomes 4 and 10, primer sets for the markers D4Mit108 (map position: 12.1 cM), D4Mit15 (42.6 cM), D4Mit54 (66.0 cM), D10Mit247 (7.0 cM), D10Mit170 (29.0 cM), and D10Mit14 (65.0 cM) were used for the initial coarse analyses and the other primers listed in Fig. 2, C and D, were additionally used for detailed analyses. PCR amplification was conducted 35 cycles with the cycling profile 94°C for 0.5 min, 55°C for 1 min, and 72°C for 1 min on the GeneAmp PCR Systems 2700 and 9600 (Applied Biosystems), and the products were run on 3% agarose gel (Agarose 21; Nippon Gene).

View larger version (46K): [in this window] [in a new window]   FIGURE 2. Mapping QTLs for skin disease severity on chromosomes 4, 10, and 16. A, Single marker association to the severe disease (score 3) for a total 226 IRF-2–/–CBF1 x BN backcrossed progeny. Markers on chromosomes 4, 10, and 16 gave highly significant association (broken line corresponds to p = 0.0005). B, Epistatic interaction between QTLs on chromosome 4 or 10 with that on chromosome 16. Skin scores of IRF-2–/–CBF1 x BN mice with different combinations of homozygosity for the C57BL/6 allele (B) and heterozygosity (H) for markers either D4Mit27 and D16Mit5 (upper panel) or D10Mit297 and D16Mit5 (lower panel). Each dot represents an individual animal. Numbers in parentheses denote the mean skin scores for mice with each combination. C and D, Interval mapping of the chromosome 4 (C) and 10 (D) loci for linkage to the disease severity. Horizontal broken line represents the LRS value (16.9) for highly significant linkage threshold as established by a permutation test. Numbers in parentheses are the map positions of markers in cM.

For nonparametric linkage analysis of the severities of skin diseases in IRF-2^–/– mice on the CBF1 x BN background, ² analysis was performed. The Map Manager QTX software (version β18; http://mapmgr.rosewellpark.org/mmQTX.html) was used to determine the likelihood ratio statistics (LRS) values for the severity of the skin disease and the frequencies of splenic CD4⁺ DC. Logarithm of the odds (LOD) scores were calculated by LRS/(2ln10). The thresholds for suggestive and significant linkage were determined by permutation test with 1000 permutations using MapManager QTX.

RNA preparation and gene expression analysis

Total RNA was prepared from the abdominal skin using guanidinium thiocyanate phenol-chloroform extraction and converted to cDNA with the ImProm-II Reverse Transcription System (Promega). Quantitative PCR analysis was conducted on a Thermal Cycler Dice Real-Time System (Takara Bio) using a SYBR Premix Ex Taq kit (Takara Bio) according to the manufacturer’s instruction for 40 cycles with denaturation at 95°C for 5 s and annealing at 60°C for 30 s. The amounts of mRNA species for various mouse strains were calculated according to those of β-actin as determined in parallel amplifications and shown as relative quantities in comparison to the standard mRNA preparation from the skin of a wild-type C57BL/6 mouse used throughout this study. PCR primers used were purchased from Takara Bio (IFN- and Ifit3), Greiner (Stat1), and Applied Biosystems (Tgtp and β-actin): IFN-, sense: 5'-CGGCACAGTCATTGAAAGCCTA-3', antisense: 5'-GTTGCTGATGGCCTGATTGTC-3'; Tgtp, sense: 5'-GTTATTGCCACCAGATCAAGGTC-3'; antisense: 5'-AAGAATGCATCAAAGCTGGAGG-3'; Ifit3, sense: 5'-TCCCAGCAGCACAGAAACAGA, antisense: 5'-TCCTCAGAGTTTAAATGTTCGACCT-3'; Stat1, sense: 5'-GACCAGCAGCCAGGGACGTTC-3', antisense: 5'-TCGTGTAGGGCTCCACGGCA-3'; β-actin, sense: 5'-GCTTCTTTGCAGCTCCTTCGT-3', antisense: 5'-AGCGCAGCGATATCGTCAT-3'.

Cell preparation and flow cytometry

Single-cell suspensions were prepared from spleens and stained with fluorescent-labeled Abs, PE-anti-CD4 (eBioscience), allophycocyanin-anti-CD8 (eBioscience), and FITC-anti-CD11c (BD Pharmingen). Stained cells were analyzed on the FC500 flow cytometer (Beckman Coulter) with RXP software (Beckman Coulter). Dead cells were regularly excluded using propidium iodide.

	Results

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Strain-dependent development of skin disease in IRF-2^–/– mice

When we backcrossed IRF-2^–/– mice to the BALB/c strain to generate IRF-2^–/–CN mice, we notice that these mice did not develop the skin disease that was previously reported to develop spontaneously in IRF-2^–/– mice with the C57BL/6 background (IRF-2^–/–BN mice; Ref. 16). Thus, none of the IRF-2^–/–CN mice exhibited any sign of inflammation such as alopecia and sclerosis macroscopically (Table I) and acanthosis, loss of s.c. fat tissue, fibrosis, and dermal/s.c. infiltration of inflammatory cells, the majority of which were F4/80⁺ macrophages, under microscopic inspection (Fig. 1). Because IRF-2^–/– mice on the BALB/c x C57BL/6 (CBF1) background also did not develop the skin disease (Table I), the genes in the BALB/c genome acted dominantly to suppress the disease promoting C57BL/6 alleles.

View larger version (109K): [in this window] [in a new window]   FIGURE 1. A, Strain-dependent development of skin inflammation in IRF-2–/– mice. Skin sections from 12-wk-old control littermates (Control) and IRF-2–/– mice (KO) backcrossed to C57BL/6 (BN) or BALB/c (CN) mice are shown. Note that thickening of the epidermis and massive infiltration of mononuclear cells are observed only in KO/BN mice. Original magnification was x30. B, Skin sections prepared from control littermates (Control/BN) and IRF-2–/–BN mice (KO/BN) were stained for the macrophage marker F4/80, showing numerous macrophage infiltration in the dermis only in IRF-2–/–BN mice. Original magnification was x40. Bars in A and B, 200 µm.

To characterize chromosomal regions suppressing the skin disease, >200 IRF-2^–/– mice on the CBF1 x C57BL/6 backcross background were generated and examined for the severity of the skin disease. One hundred eighty-eight animals of 226 examined developed the skin disease with the severities varying considerably (Table I), suggesting multiple QTLs involved in the suppression of the phenotype. Because we have never observed spontaneous reversion of the IRF-2 mutation during maintenance of the IRF-2^–/– strain over more than a decade, it was virtually impossible that the absence of the skin disease or less severe pathology in these backcross offspring involved such a mechanism. Through initial genotyping of these backcrossed offspring, we identified a highly significant association of the severe disease (score 3) to the loci on chromosomes 4 (p = 2.3 x 10^–8) and 10 (p = 6.5 x 10^–5) together with less strongly associated loci such as those on chromosomes 1, 2, and 16 (Fig. 2A). We did not observe any significant linkages to the onset of the skin disease (score >0). Interestingly, a locus on chromosome 16 (p = 1.9 x 10^–4, Fig. 2A) was associated with the severity of the skin disease in a fashion epistatic to those on chromosomes 4 and 10 (Fig. 2B). Thus, IRF-2^–/– mice homozygous (B) for C57BL/6 at D4Mit27 marker and heterozygous (H) at D16Mit5 developed most severe skin disease (Fig. 2B). These results indicated that the mode of the control of skin disease severity was complex in which multiple loci influenced both positively and negatively on the skin disease severity.

Upon further characterization of the loci on chromosomes 4 and 10 using additional primer sets, QTLs affecting the skin disease severity were identified. The peaks of LRS as obtained by simple interval mapping at 1-cM intervals were between D4Mit327 (map position 42.5 cM according to Mouse Genome Informatics; www.informatics.jax.org) and D4Mit187 (49.6 cM) markers and between D10Mit35 (69.0 cM) and D10Mit297 (70.0 cM) markers on chromosomes 4 and 10, respectively (Fig. 2, C and D). Peak LRS values were 39.0 and 29.6, corresponding to LOD scores 8.5 and 6.4, for the loci on chromosomes 4 and 10, respectively. These results indicated that at least these two strong loci derived from BALB/c mice down-modulated the skin disease severity in IRF-2^–/– mice.

The frequencies of CD4⁺ DC in IRF-2^–/– mice were affected by the loci distinct from that which controlled the skin disease severity

The other phenotype of IRF-2^–/–BN mice so far known to be IFN-/IFN-β dependent was the defective development of CD4⁺ DC (20). As shown in Fig. 3, A and B, IRF-2^–/–CN and IRF-2^–/–CBF1 mice, neither of which develop the skin disease (Table I), did not show such abnormalities in the DC population in the spleen. To examine whether the loci modulating the skin disease severity also contributed to this strain-dependent CD4⁺ DC defect, linkage analyses were conducted using these IRF-2^–/– backcross offspring (n = 80). A single strongly linked locus on chromosome 4 (p = 5.7 x 10^–5) and several weaker linkages to loci on chromosomes 6, 7, 14, and 16 (Fig. 3C) were identified for the degrees of the CD4⁺ DC defect, whereas no significant linkage was observed on chromosome 10 (Fig. 3C). Interval mapping for QTL affecting the degrees of the DC defect revealed that the peak LRS value for the locus was 20.3 (LOD = 4.4), reached between the markers D4Mit204 (map position 61.9 cM) and D4Mit54 (66.0 cM) (Fig. 3D). Interestingly, only a much less significant association (p > 10^–3) was observed for the marker D4Mit27 (42.5 cM) that exhibited strong link to the skin disease severity (Fig. 2C). These observations indicated that the degrees of the CD4⁺ DC defect were principally influenced by the loci distinct from those affecting the skin disease severity.

View larger version (29K): [in this window] [in a new window]   FIGURE 3. CD4+ DC defect in IRF-2–/– mice was controlled by loci distinct from those for the skin disease severity. A, Flow cytograms for CD4 and CD8 of CD11c+ splenic DCs prepared from mice with the indicated genotypes and backgrounds are shown. Numbers represent the percentages of cells within the quadrants. B, Frequencies of CD4+ and CD8+ subsets within CD11c+ splenic DCs are plotted for control littermates and IRF-2–/– mice with the indicated backgrounds. Each circle represents an individual mouse. Horizontal bars are for the mean. C, Single marker association to the CD4+ DC frequencies with the cutoff value 38% for IRF-2–/–CBF1 x BN backcrossed progeny (n = 80). Only a marker on chromosomes 4 gave highly significant association (broken line corresponds to p = 0.0005). D, Interval mapping of the chromosome 4 locus for linkage to the CD4+ DC frequencies. Horizontal broken line represents the LRS value (16.1) for highly significant linkage thresholds as established by a permutation test. Numbers in parentheses are the map positions of markers in cM.

Influence of the genetic background on spontaneous IFN-/IFN-β responses in the skin in IRF-2^–/– mice

Interestingly, the skin disease-modifying QTL present on a relatively centromeric position on chromosome 4 spanned the IFN gene cluster including genes for multiple species of type I IFNs. Because skin disease development in IRF-2^–/–BN mice was totally dependent on IFN-/IFN-β signals (16), one or more type I IFN genes might possibly be responsible for the QTL. RT-PCR examination using a common set of primers for IFN- species did not show, however, elevation of IFN- expression associated with IRF-2 deficiency (16). Accordingly, we did not observe significant difference in IFN-/IFN-β expression in the skin between IRF- 2^–/–BN and IRF-2^–/–CN mice (F. Arakura, unpublished observation). We next examined spontaneous IFN-/IFN-β responses in the skin in IRF-2^–/–BN, IRF-2^–/–CN, and IRF-2^–/–CBF1 mice by quantifying the amounts of mRNA for the well-known IFN-inducible genes Ifit3 (IFN-inducible protein with tetratricopeptide repeat 3; Ref. 24) and Tgtp (T cell-specific GTPase; Ref. 25) by real-time RT-PCR. As shown in Fig. 4, spontaneous IFN-/IFN-β responses were >10-fold higher in IRF-2^–/–BN mice compared with those in their heterozygous (IRF-2^+/–) control mice in agreement with the previous report (16), while they were elevated to much lesser extents, if not completely abolished, in IRF-2^–/–CN and IRF-2^–/–CBF1 mice than in control CN and CBF1 mice. These results indicated that one or more genetic elements in BALB/c mice conferred IRF-2^–/– mice tolerance to the absence of IRF-2 with respect to spontaneous IFN-/IFN-β responses.

View larger version (22K): [in this window] [in a new window]   FIGURE 4. Strain-dependent acceleration of spontaneous IFN-/IFN-β responses in IRF-2–/– mice. IFN-/IFN-β responses as represented by the relative amounts of Ifit3 (A) and Tgtp (B) messages in the skin determined by real-time PCR are shown for mice with the indicated genetic backgrounds. Each symbol represents an individual mouse. Horizontal bars are for the mean. Significantly elevated in IRF-2–/– mice compared with control mice: **, p < 0.005 and *, p < 0.05 by Mann-Whitney U test.

Effects of genetic background on the spontaneous expression of IFN- in the skin in IRF-2^–/– mice

The QTL on chromosome 10 spanned various cytokine genes previously proposed to play pathogenic roles in skin inflammation, such as those for IL-22, IL-23p19, and IFN-. We observed, however, that IL-22 messages were virtually undetectable in the skin in both IRF-2^–/– and control mice (at least <1/100 of the levels in T cells from TCR-transgenic mice stimulated with cognate antigenic peptides; F. Arakura and S. Hida, unpublished observation). In addition, the levels of IL-23p19 messages in the skin in IRF-2^–/–BN mice were not altered compared with those in control mice (F. Arakura, unpublished observation). In contrast, the amounts of IFN- mRNA in the skin in IRF-2^–/–BN mice were spontaneously elevated 10-fold compared with those in control mice (Fig. 5A). By contrast, we did not observe such an elevated expression of IFN- messages at all, both in IRF-2^–/–CN and IRF-2^–/–CBF1 mice (Fig. 5A), indicating that the expression of IFN- in the skin in the absence of IRF-2 was under control by the genetic background. Stat1 expression, which was IFN- inducible (26), also increased in IRF-2^–/–BN mice but in neither IRF-2^–/–CN nor IRF-2^–/–CBF1 mice, compared with control animals with corresponding genetic backgrounds (Fig. 5B). Furthermore, IRF-2^–/–BN mice with concomitant mutations in RAG-1 or β₂m, both of which were free from the skin disease (our unpublished observation and Ref. 16), did not exhibit such up-regulation, but rather exhibited even reduction of IFN- messages compared with RAG-1^–/– or β₂m^–/– mice (Fig. 5C). The reduction in IFN- expression was perhaps due to the impaired maturation of NK cells (18). Because both RAG-1^–/–IRF-2^–/– and β₂m^–/–IRF-2^–/– double mutant mice commonly lacked CD8⁺ T cells, the elevated IFN- messages in the skin in IRF-2^–/–BN mice appeared to be derived from CD8⁺ T cells.

View larger version (30K): [in this window] [in a new window]   FIGURE 5. Strain-dependent up-regulation of the expression of CD8+ T cell-derived IFN- in IRF-2–/– mice. The relative amounts of the messages for IFN- (A and C) or Stat1 (B) in the skin are shown for mice with the indicated genetic backgrounds. Each symbol represents an individual mouse. Horizontal bars are for the mean. Significantly elevated in IRF-2–/– mice compared with control mice: **, p < 0.005 and *, p < 0.01 by Mann-Whitney U test.

Delayed and infrequent skin disease in IFN- receptor-deficient IRF-2^–/– mice

The observations above prompted us to directly examine the pathogenic role of IFN- in the skin disease in IRF-2^–/– mice, and we generated IRF-2^–/–BN mice lacking the -chain of IFN- receptor (IFNGR1). Upon macroscopic inspection, while most of IRF-2^–/–BN mice already started to develop clearly visible skin disease at the age of 7–8 wk and developed fully established skin lesion at 10–15 wk after birth, the majority of IRF-2^–/–BN mice lacking the IFN- receptor (IFNGR1^–/–IRF-2^–/–BN mice) did not show any macroscopic signs of inflammation (Fig. 6A). Under microscopic inspection, no obvious thickening of the epidermis was seen in these animals (Fig. 6B, "IFNGR1^–/–IRF-2^–/–"). Although occasional infiltration of mononuclear cells could be noticed in s.c. fat tissue, overall architecture of the skin was well-preserved otherwise. In contrast to IRF-2^–/– mice lacking the IFN-/IFN-β receptor (IFNAR1^–/–IRF-2^–/– BN mice) or β₂m (β2m^–/–IRF-2^–/–BN mice), which never developed the skin disease (16), those lacking the IFN- receptor were, however, not totally free from the skin disease as some animals did develop the disease when they became very old, albeit far infrequently compared with IRF-2^–/–BN mice; less than one of five animals developed visible but relatively milder disease at the age of 15–20 wk (Fig. 6A and S. Taki, unpublished observation). These results clearly indicated that IFN- was important, yet not essential, for the onset and progression of the skin disease, and excluded the possibility that IFN- up-regulation in the skin was a result of local inflammation.

View larger version (68K): [in this window] [in a new window]   FIGURE 6. Delayed and infrequent development of skin disease in IRF-2–/– mice lacking the IFN- receptor. A, Skin disease scores at the indicated age of weeks are plotted. Cumulative data for five animals of each genotype. Not all mice were examined at each time point. B, Skin sections from 14-wk-old IRF-2+/– (Control), IFNGR1+/–IRF-2–/– (IRF-2–/–), and IFNGR1–/–IRF-2–/– mice on the BN background were stained with H&E. Note the infiltration of mononuclear cells in IFNGR1–/–IRF-2–/– mice. Original magnification was x30. Bars, 200 µm.

IFN- up-regulation as an event downstream of aberrant IFN-/IFN-β signals

Spontaneous IFN-/IFN-β responses as measured by Ifit3 expression remained to be elevated in the skin in IFN- receptor-deficient IRF-2^–/–BN mice, while such an elevation was no longer observed in IFN-/IFN-β receptor-deficient IRF-2^–/–BN mice (Fig. 7A). Tgtp expression also remained to be elevated significantly (p < 0.05) in IFN- receptor-deficient IRF-2^–/–BN but not in IFN-/IFN-β receptor-deficient IRF-2^–/–BN mice compared with mice lacking IFN- receptor and IFN-/β receptor alone, respectively (Fig. 7B). Less prominent Tgtp up-regulation than that of Ifit3 in IFN- receptor-deficient IRF-2^–/–BN mice compared with IRF-2^–/–BN mice (Fig. 7B) perhaps reflected the potential inducibility of Tgtp both by IFN- and IFN-/IFN-β (25). Unlike these IFN-inducible genes, IFN- and Stat1 expression in the skin was not elevated at all in IFN-/IFN-β receptor-deficient IRF-2^–/–BN mice compared with IFN-/IFN-β receptor-deficient control mice (Fig. 7, C and D). Up-regulation of Stat1 but not IFN- itself was dependent on the IFN- receptor (Fig. 7, C and D), further supporting the functional relevance of IFN- up-regulation. These observations together indicated that IFN- up-regulation in the skin was an event downstream of IFN-/IFN-β responses but not vice versa.

View larger version (39K): [in this window] [in a new window]   FIGURE 7. IFN- up-regulation is an event downstream of aberrant IFN-/IFN-β responses in IRF-2–/– mice. Shown are the relative amounts of the messages for Ifit3 (A), Tgtp (B), IFN- (C), and Stat1 (D) in the skin isolated from control (C) and mice lacking the IFN-/IFN-β receptor (AR1–/–) or IFN- receptor (GR1–/–). Each symbol represents an individual mouse. Horizontal bars are for the mean. Significantly elevated in IRF-2–/– mice compared with control mice: **, p < 0.005 and *, p < 0.05 by Mann-Whitney U test.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion Disclosures References

In IRF-2^–/– mice, the CD4⁺ DC defect was not only dependent on IFN-/IFN-β signals (16, 20, 22) but also was under the influence of the genetic background where the BALB/c genome dominantly repressed the manifestation of the phenotype. However, current linkage analysis revealed that the major loci controlling the DC phenotype were distinct from those influencing the severity of the skin disease, suggesting that the DC defect was not the mechanism critical for the skin disease and conceivably represented another outcome of aberrant IFN-/IFN-β signals, an interesting issue from the point of view of the mechanism for DC subset development (27).

As pathogenic events that were under the strain-dependent genetic control, we found two cytokine-related abnormalities in IRF-2^–/– mice: the up-regulation in spontaneous IFN-/IFN-β responses and IFN- expression in the skin. The IFN- up-regulation appeared to be an event downstream of the accelerated IFN-/IFN-β responses, leading to the augmented expression of its target Stat1 and ultimately to the development of the skin disease. Thus, the QTLs on chromosomes 4 and 10 might control the disease severity through modulating the magnitude of spontaneous IFN-/IFN-β responses. The QTL for the severity of the skin disease on chromosome 4 contained the type I IFN gene cluster comprised of >10 IFN-/IFN-β genes. However, the levels of IFN-/IFN-β expression were not altered in IRF-2^–/– mice compared with control mice, at least as accessed by PCR primers common for most type I IFN species (Ref. 16 and F. Arakura, unpublished observation). Furthermore, it was reported that the type I IFN gene cluster on chromosome 4 was not responsible for the amounts of biologically active IFN-/IFN-β to be produced upon viral infection (28). These observations made unlikely the possibility that the type I IFN cluster itself controlled IFN-/IFN-β responses by modulating the amounts of spontaneously produced IFN-/IFN-β. The disease-modifying QTL on chromosome 4 also contained the genes for the transcription factor Jun (map position 44.6 cM) that could potentially be involved in IFN-/IFN-β responses, while the QTL on chromosome 10 spanned the gene encoding Stat2 (map position 70.0 cM), an intracellular signal transducer for IFN-/IFN-β. Although these genes were possible candidates for the QTLs, these QTL-encompassing regions were still so large that they covered considerable numbers of genes including those to which no obvious function has been assigned, and we have to further narrow down the QTL regions before we can identify plausible candidates.

It is notable that spontaneous IFN-/IFN-β responses in IRF-2^–/–CBF1 mice were much lower than those in IRF-2^–/–BN mice, but still considerably higher than those in IRF-2^–/–CN mice. In contrast, IFN- up-regulation was almost totally absent in not only IRF-2^–/–CN but also IRF-2^–/–CBF1 mice. These results suggested that yet another background gene(s) interfered with IFN- up-regulation, even if IFN-/IFN-β responses were accelerated considerably. With respect to IFN- expression, the QTL on chromosome 10 encompassed the gene for IFN- (map position: 67.0 cM). However, polymorphisms in the Ifng gene itself, regardless of whether these, if any, were in the coding or regulatory regions, appeared to be unable to account for the dominant nature of the BALB/c allele, because the putative BALB/c-derived gene(s) seemed to repress the expression of the C57BL/6-derived Ifng allele in IRF-2^–/–CBF1 mice in a "trans-acting" manner. Thus, we consider that background gene(s) distinct from the Ifng gene itself, yet to be identified, modulated IFN- expression in the skin in conjunction with IRF-2. Nevertheless, both the skin disease and IFN- expression in the skin were influenced by the background genes in a manner where the BALB/c genome dominantly repressed both phenotypes, suggesting a possibility that a set of background genes influenced the skin disease severity through regulating the IFN- expression. Another set of large scale genome-wide scan should be undertaken to determine directly whether these QTLs on chromosomes 4 and 10 controlled IFN-/IFN-β responses and IFN- expression in the skin. Those background genes, whatever they might be, seemed to constitute a fail-safe device for the homeostasis of the skin immune system, functioning to compensate for the absence of IRF-2. It is an intriguing possibility, of course yet to be proven, that possible human counterparts of these murine genes would negate the effect of, if any, IRF-2 malfunctions in the pathogenesis of human psoriasis (6, 7).

IFN- expressed in the skin in IRF-2^–/–BN mice appeared to be derived from CD8⁺ T cells and, in fact, played a critical role in the cutaneous pathogenesis in these mice as demonstrated by the delayed and infrequent skin disease development in IFN- receptor-deficient IRF-2^–/–BN mice. It was shown that circulating CD8⁺ T cells showed "memory" phenotypes in IRF-2^–/– mice (16), reminiscent of the infiltration of CD8⁺ T cells of "memory/activated" phenotypes (29, 30) that could produce IFN- (31, 32) in human psoriasis lesions. IFN- expression was accordingly detected in the lesional skin in psoriasis patients (33) and reduced upon therapy (34), providing support for the hypothesis that psoriasis is a "type 1 disease" (13). Our current findings are also in line with the hypothesis that IFN- production by memory/activated CD8⁺ T cells in psoriatic plaques was downstream of enhanced IFN-/IFN-β responses (9). Production of IFN- by CD8⁺ T cells as up-regulated by aberrant IFN-/IFN-β signals might be directly induced (35) through activation of Stat4 in T cells (9) or alternatively mediated by other cell types such as DCs (36), possibly via IL-15. IL-15 is the cytokine that was shown to be produced from DCs upon IFN-/IFN-β stimulation (37) and plays roles in the maintenance of memory phenotype CD8⁺ T cells (38). Interestingly, the pathogenic role of IL-15, the gene for which is within the PSORS3 loci, was indeed implicated in a xenogenic model for psoriasis (39).

The cytokine IL-22 and cytokine subunit IL-23p19, the genes for which are interestingly included in the chromosome 10 QTL (map positions 67.0 and adjacent to the Stat2 gene, respectively), were also recently implicated in human psoriasis as well as in murine skin inflammation (34, 40, 41, 42, 43), suggesting the involvement of the so-called Th17, at least partly, in skin inflammation. In this study, however, we failed to detect IL-22 messages in the skin in both control and IRF-2^–/–BN mice, and cutaneous IL-23p19 expression was as low in IRF-2^–/–BN mice as in wild-type controls (F. Arakura and S. Hida, unpublished observation). It is possible that IRF-2^–/–BN mice and the IL-23-elicited skin inflammation model (40) represent two extreme aspects of skin inflammation that might contribute in concert to the establishment of skin lesions in human psoriasis. Alternatively, these two groups of cytokines might not act simultaneously but contribute to distinct stages of skin inflammation in humans as both IFN-/IFN-β and IFN- could inhibit Th17 differentiation (40, 44). In favor of the latter, IFN-/IFN-β production in a xenogenic model of psoriasis was reported to be transient and restricted to the early stages of psoriasis development (12). In this regard, the pathogenic roles of CD8⁺ T cells and IFN-/IFN-β in the skin inflammation in IRF-2^–/–BN mice were not absolutely confined to the IFN- up-regulation because IRF-2^–/–BN mice lacking the IFN-/IFN-β receptor or β₂m did not show any sign of skin inflammation even when they were very old (16), contrary to IFN- receptor-deficient IRF-2^–/–BN mice that were not completely free from the skin disease. These observations suggested that IFN-/IFN-β seemed to play additional auxiliary roles in the skin disease in IRF-2^–/–BN mice, conceivably through activating CD8⁺ T cell functions other than IFN- production, where IL-22 and/or IL-23 could be involved.

IRF-2^–/– mice are unique among other animal models for human psoriasis such as epidermal IKK2- or Jun-deficient and K5-Stat3C-transgenic mice in which the pathogenic roles of IFN-/IFN-β and IFN- were unclear or irrelevant (45, 46, 47). We infer that these animals modeled the pathogenic events induced in keratinocytes by IFN-, whereas IRF-2 deficiency initiated the pathogenic process at a much earlier step. Regardless of the stages at which these genetic manipulations initiated the pathogenic process, one of the endpoints seemed to be prominent macrophage infiltration in the skin in not only IKK2-deficient and CD18 hypomorphic models (48, 49), but also in IRF-2^–/–BN mice (Fig. 1B). Occasional infiltration of mononuclear cells without evoking inflammation in IFN- receptor-deficient IRF-2^–/–BN mice might suggest that the role of IFN- was to activate these cells for inflammation rather than to induce their infiltration.

In conclusion, our current study showed that IFN-/IFN-β, which could be produced spontaneously or upon stimulation with environmental cues such as viral or bacterial infections, led to up-regulated expression of IFN- by CD8⁺ T cells unless appropriately regulated by IRF-2 only in individuals who lacked the reinforcements for the homeostatic regulation of the IFN-/IFN-β system due to genetic variations. Control of IFN-/IFN-β responses by both IRF-2 and the background genes may provide the basis for the clinical observations that only a fraction of patients of other diseases developed or exacerbated psoriasis upon treatment with a high dose of IFN-/IFN-β (50, 51, 52). Thus, IRF-2^–/– mice will be useful to understand the highly complex pathogenic mechanism in skin inflammations in which these cytokines have been implicated.

	Acknowledgments

 
We thank Drs. Sachiko Hirose and Mamoru Ito for their invaluable advice at the initiation of this study, and Yukie Takeoka and the late Namiko Azuta for their excellent technical assistance.

	Disclosures

Top Abstract Introduction Materials and Methods Results Discussion Disclosures References

 
The authors have no financial conflict of interest.

	Footnotes

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by a Grant-in-Aid for Scientific Research on Priority Area (18060016) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, a Grant-in-Aid (19590494) from the Japan Science Promotion Society, and a grant from the Naito Foundation.

² Address correspondence and reprint requests to Dr. Shinsuke Taki, Department of Immunology and Infectious Diseases, Graduate School of Medicine, Shinshu University, 3-1-1 Asahi, Matsumoto 390-8621, Japan. E-mail address: shin-t{at}sch.md.shinshu-u.ac.jp

³ Abbreviations used in this paper: IRF-2, IFN regulatory factor-2; DC, dendritic cell; QTL, quantitative trait locus; LRS, likelihood ratio statistics; LOD, logarithm of the odds; β₂m, β₂-microglobulin.

Received for publication May 15, 2007. Accepted for publication June 21, 2007.

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Top Abstract Introduction Materials and Methods Results Discussion Disclosures References

 

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