Dendritic CellsPsoriasis by Restricting MyD88 Signals in Cutting Edge: ABIN-1 Protects against
Rosenblum, Barbara A. Malynn and Averil MaD.Jonathan Paw, Julio Barrera, Anthony DeFranco, Michael
Rommel Advincula, Nataliya Shifrin, Hong-An Truong,Agelides, Bao H. Duong, Shigeru Oshima, Jeffrey North, Joseph A. Callahan, Gianna E. Hammer, Alexander
Cutting Edge: ABIN-1 Protects against Psoriasis byRestricting MyD88 Signals in Dendritic CellsJoseph A. Callahan,* Gianna E. Hammer,* Alexander Agelides,*Bao H. Duong,* Shigeru Oshima,* Jeffrey North,† Rommel Advincula,*Nataliya Shifrin,* Hong-An Truong,† Jonathan Paw,† Julio Barrera,*Anthony DeFranco,‡ Michael D. Rosenblum,† Barbara A. Malynn,* andAveril Ma*
Psoriasis is a chronic, inflammatory skin disease causedby a combination of environmental and genetic factors.The Tnip1 gene encodes A20 binding and inhibitor ofNF-kB-1 (ABIN-1) protein and is strongly associatedwith susceptibility to psoriasis in humans. ABIN-1,a widely expressed ubiquitin-binding protein, restrictsTNF- and TLR-induced signals. In this study, we re-port that mice lacking ABIN-1 specifically in dendriticcells (DCs), ABIN-1fl CD11c-Cre mice, exhibit perturbedimmune homeostasis. ABIN-1–deficient DCs displayexaggerated NF-kB and MAPK signaling and producemore IL-23 than do normal cells in response to TLRligands. Challenge of ABIN-1fl CD11c-Cre mice withtopical TLR7 ligand leads to greater numbers of Th17and TCRgd T cells and exacerbated development ofpsoriaform lesions. These phenotypes are reversed byDC-specific deletion of the TLR adaptor MyD88.These studies link ABIN-1 with IL-23 and IL-17,and they provide cellular and molecular mecha-nisms by which ABIN-1 regulates susceptibility topsoriasis. The Journal of Immunology, 2013, 191:535–539.
Psoriasis is a common immune-mediated skin disorderwhose complex pathophysiology involves environ-mental factors, including microbes, as well as host
susceptibility factors, including genetically determined im-munologic propensities (1, 2). Recent genome-wide associa-tion studies have highlighted potential roles of specificproteins in disease pathogenesis, including HLA-C, IL-12b,TNIP1/A20 binding and inhibitor of NF-kB-1 (ABIN-1),TNFAIP3/A20, IL-23a, and IL-23R (3). Some of thesepolymorphisms are also linked to therapeutic responses of
psoriasis patients to specific therapies (4). These findingsemphasize the immunological nature of psoriasis and impli-cate specific immune functions, such as HLA-C–mediatedAg presentation and IL-12/IL-23–dependent innate immunesignals. Because innate immune cells such as dendritic cells(DCs) are outstanding APCs, and because IL-12 and IL-23are secreted by innate immune cells to amplify T cell acti-vation and differentiation events, these genetic clues suggestthat aberrant DCs and T cell functions are integral to pso-riasis.TNIP1, which encodes the ABIN-1 protein, is strongly
linked to psoriasis in both European (combined genome-widep value of 13 10220) and Chinese (combined genome-wide pvalue of 3.8 3 10221) populations (5–7). ABIN-1 restrictsseveral NF-kB signaling cascades and regulates cell survival(8–12). In vitro studies suggest that ABIN-1 can bindNEMO/IKKg and inhibit TNF-induced NF-kB signaling(13). ABIN-1 can also bind ubiquitin chains, and ubiquitinbinding by ABIN-1 is important for the ability of ABIN-1to restrict TNF and TLR signals (11, 12). Global loss or mu-tation of ABIN-1 leads to either embryonic lethality or spon-taneous inflammation and autoimmunity (11, 12, 14). Thesestudies indicated that ABIN-1 plays critical roles in regulatingTNF and TLR signals. However, the mechanisms by whichABIN-1 regulates physiological immune homeostasis and pso-riasis susceptibility are unknown.DCs have long been recognized as important cells for
triggering immune responses during overt immunizations orinfections (15). Recent studies suggest that DCs also preserveimmune homeostasis under basal conditions (16–21). DCsmay regulate susceptibility to psoriasis by secreting type IIFNs, TNF, or other proinflammatory cytokines, as well as bystimulating skin T cells (22). Given the potential importanceof DCs to immune homeostasis in the skin and the potentialimportance of ABIN-1 polymorphisms to psoriasis, we have
*Department of Medicine, University of California, San Francisco, San Francisco, CA94143; †Department of Dermatology, University of California, San Francisco, SanFrancisco, CA 94143; and ‡Department of Microbiology and Immunology, Universityof California, San Francisco, San Francisco, CA 94143
Received for publication December 14, 2012. Accepted for publication May 13, 2013.
This work was supported by grants from the National Institutes of Health (to A.M.) andby the Histopathology and Immunology Cores of the University of California, SanFrancisco Liver Center. G.E.H. was supported by National Institutes of Health GrantT32 DK007007. J.A.C. was partially supported by a National Science Foundationpredoctoral fellowship.
Address correspondence and reprint requests to Prof. Averil Ma, University of Califor-nia, San Francisco, 513 Parnassus Avenue, S-1057, San Francisco, CA 94143-0451.E-mail address: [email protected]
The online version of this article contains supplemental material.
Abbreviations used in this article: ABIN-1, A20 binding and inhibitor of NF-kB-1;BMDC, bone marrow–derived dendritic cell; cDC, conventional dendritic cell; DC,dendritic cell; IMQ, imiquimod; pDC, plasmacytoid dendritic cell.
Copyright� 2013 by TheAmerican Association of Immunologists, Inc. 0022-1767/13/$16.00
investigated whether ABIN-1 expression in DCs may regulatepsoriasis susceptibility.
Materials and MethodsMice
The initial targeting of the Tnip1 (ABIN-1) gene in C57BL/6N PRX-B6Tembryonic stem cells was previously described (11). ABIN-1–targeted em-bryonic stem cells were transfected with an EF1a-Cre expression construct(20), and colonies were screened for deletion of the neomycin gene and re-tention of ABIN-1 exons 12–15 flanked by LoxP sites (floxed allele). Gen-otypes were confirmed both by Southern blot analyses and by PCR (primers:59-TTGATTCCCCTTCGCCCATTCCAGC-39, 59-CCTCAAACAGCA-GAAGAGGAAAGC-39, and 59-ATGGGTGGGTAGGCATAGGGATAG-39). MyD88fl mice were described previously (23). All mouse experimentswere approved by the University of California, San Francisco InstitutionalCare and Use Committee.
Cell preparation and analyses
Cell preparations and flow cytometric analyses were performed as previouslydescribed (20). Immunoblots were performed as described (11). Abs to sur-face markers (BD Biosciences), actin (Calbiochem), phospho-IkBa, IkBa,phospho-Erk, Erk, phospho-JNK, and JNK (Cell Signaling Technologies)were purchased.
Imiquimod treatment and scoring of skin inflammation
Imiquimod (IMQ) treatments were performed largely as previously described(24, 25). Mice received a daily topical dose of 12.5 mg IMQ cream (5%)(Perrigo) or lotion control for 12 consecutive days. Skin inflammation wasscored using a previously described scoring system (24). Histological sectionswere prepared by the University of California, San Francisco Veterans AffairsMedical Center Pathology Core.
Results and DiscussionTo investigate whether ABIN-1 expression in DCs regulatesimmune functions in vivo, we generated mice bearing LoxPsites flanking exons 12–15 of ABIN-1 (ABIN-1fl) mice andbred them with CD11c-Cre transgenic mice to create micelacking ABIN-1 in DCs (Supplemental Fig. 1A) (26). ABIN-1fl/fl CD11c-Cre mice appeared grossly normal for up to 6 moof age. Conventional DCs (cDCs; CD11chiMHC class II+)and plasmacytoid DCs (pDCs; CD11cloB220hi) were presentin slightly elevated numbers in spleens from ABIN-1fl/fl
CD11c-Cre mice (Fig. 1A). These cells expressed relativelynormal levels of activation markers, with the exception ofminimally elevated levels of CD40 on cDCs and slightlylower CD80 levels on pDCs (Supplemental Fig. 1B, 1C).Thus, ABIN-1 expression in DCs is not required for DCdevelopment but modestly regulates DC activation underbasal conditions. ABIN-1fl/fl CD11c-Cre mice developedsplenomegaly and lymphadenopathy by 3–4 mo of age, ac-cumulating myeloid (CD11b+Gr-1+) cells and memory phe-notype T cells (Fig. 1B–D and data not shown). Thus, ABIN-1expression in DCs preserves myeloid and lymphoid immunehomeostasis.DCs are activated by TLR ligands during overt immuni-
zations and infections and may also respond to MyD88-dependent signals under basal conditions (20). We askedwhether ABIN-1 preserves immune homeostasis by restrictingMyD88-dependent signals in DCs by generating compoundABIN-1fl/flMyD88fl/fl CD11c-Cre mice that lack bothABIN-1 and MyD88 specifically in DCs. Remarkably, incontrast to ABIN-1fl/fl CD11c-Cre mice, the spontaneousaccumulation of myeloid cells and activated T lymphocytesobserved in ABIN-1fl/fl CD11c-Cre mice was abrogated inABIN-1fl/flMyD88fl/fl CD11c-Cre mice (Fig. 2, SupplementalFig. 2A, 2B). Thus, ABIN-1 restricts basal Myd88-dependent
intracellular signals in DCs, thereby preserving immune ho-meostasis in unperturbed mice.To determine how ABIN-1 restricts MyD88-dependent
signals in DCs, we tested the responses of ABIN-12/2 andABIN-1+/+ bone marrow–derived DCs (BMDCs) to theTLR4 ligand LPS. LPS-stimulated ABIN-12/2 BMDCs se-creted more TNF, IL-6, IL-12, and IL-23 than did controlBMDCs (Supplemental Fig. 2D). This is consistent with
FIGURE 1. ABIN-1 expression in DCs is necessary to preserve immune
homeostasis. (A) Flow cytometric quantitation of MHC class II+CD11chi
cDCs and MHC class II+CD11cdimB220+ pDCs in spleens from indicated
mice. (B) Spleens from indicated mice. (C) Flow cytometric analyses of
myeloid, T cell, and B cell splenic subpopulations. (D) Quantitation of naive
(CD44lo) and memory phenotype (CD44hi or m.p.) T cells. Error bars
represent SEM. Open bars indicate ABIN-1+/+ CD11c-Cre+ mice; shaded
bars indicate control ABIN-1fl/fl CD11c-Cre+ mice. Data are representative of
five to six pairs of 8- to 16-wk-old mice in three to seven independent
experiments. *p , 0.05 by Student t test.
FIGURE 2. ABIN-1 restricts MyD88-dependent signals in DCs. (A) Spleen
mass of indicated genotypes. (B) Number of myeloid cells in spleens of in-
dicated mice determined by flow cytometry. (C and D) Number of memory
phenotype CD4+ (C) and CD8+ (D) T cells in pooled axillary, brachial, and
inguinal lymph nodes. All mice are CD11c-Cre+. Error bars represent SEM.
All data are representative of three independent experiments. *p , 0.05 by
Student t test.
536 CUTTING EDGE: ABIN-1 EXPRESSION IN DCs PROTECTS AGAINST PSORIASIS
a recent report showing that ABIN-1 restricts TLR-inducedIL-6 and TNF (12). Importantly, our current study implicatesABIN-1 in restricting IL-23 production by DCs. After LPSstimulation, ABIN-12/2 BMDCs also exhibited exaggeratedNF-kB, JNK, and p38 (but not ERK) signaling when com-pared with control BMDCs (Supplemental Fig. 2C). Hence,ABIN-1 regulates TLR responses in DCs by restricting TLR-induced NF-kB and MAPK signals.Given the genetic linkage of ABIN-1 to psoriasis and the
exaggerated production of IL-12 and IL-23 by ABIN2/2DCs,we asked whether ABIN-1 expression in DCs regulates sus-ceptibility to experimental psoriasis. Topical treatment withthe TLR7 ligand IMQ can cause a psoriasis-like condition inhumans and causes similar lesions in mice. This is now an
FIGURE 3. ABIN-1 restricts IMQ responses in DCs and prevents exper-
imental psoriasis. (A) Clinical scores of IMQ-induced skin inflammation in
ABIN-1fl/fl CD11c-Cre+ and ABIN-1+/+ CD11c-Cre+ (control) mice at in-
dicated days of IMQ treatment. (B–G) H&E-stained sections of back skin of
mice of indicated genotypes from areas treated with IMQ. Epithelial layer
(epi) is indicated by brackets (B–G). Epidermal hyperplasia (thickening of
epidermal layer) is evident in ABIN-1fl/fl mice (C, E, G) compared with
ABIN-1+/+ mice (B, D, F). In (C), (E), and (G), open arrows show hyper-
keratotic scaling. In (E), broad areas of hypogranulosis (abnormal loss of
purple keratohyaline granules in the skin’s granular layer) are indicated by
closed arrows. In (G), neutrophils (blue arrow) and parakeratosis (abnormal
retention of nuclei in the outermost layer of skin, green arrow) are shown in
Munro’s microabscess (dotted boxed area). Scale bar, 0.1 mm for (D)–(G).
Scale bar, 0.5 mm for (B) and (C). (H) ELISA and multiplex Luminex
analyses of cytokine production from BMDCs after treatment with the in-
dicated doses of IMQ. (I) Numbers of CD3+ and CD4+ T cells from skin-
draining lymph nodes from IMQ-treated mice of indicated genotypes.
Numbers of Th17 (CD4+IL-17+), TCRg/d+ (CD3+GL-3+), and Th1
(CD4+IFN-g+) T cells from skin-draining lymph nodes from IMQ-treated
mice. Distinct Th2 (CD4+IL-4+) populations were not detected. All mice in
(A)–(G) and (I) are CD11c-Cre+ radiation chimera. All data are representative
of three to seven independent experiments. Error bars represent SD. *p ,0.05 by Student t test.
FIGURE 4. ABIN-1 restricts MyD88 signals in DCs to prevent IMQ-in-
duced psoriasis. (A) Clinical skin inflammation scores in the indicated gen-
otypes of mice at the indicated days of IMQ treatment. (B) H&E-stained
sections of back skin of mice of indicated genotypes after treatment. Epithelial
layer denoted by brackets and “epi.” Note that skin inflammation in ABIN-
1fl/flMyD88+/+ mice is abrogated in ABIN-1fl/flMyD88fl/fl mice. All mice are
CD11c-Cre+. Error bars represent SD. *p , 0.05 by Student t test. Scale bar,0.1 mm. Data are representative of three independent experiments.
established mouse model of psoriasis (24, 27). To investigatethe functions of radiation-sensitive DCs, we generated radi-ation chimera bearing hemopoietic stem cells from ABIN-1fl/fl
CD11c-Cre or ABIN-1+/+ CD11c-Cre mice. Treatment ofmice with IMQ caused markedly increased erythema, scaling,and skin thickening in ABIN-1fl/fl CD11c-Cre chimera,which combine to yield increased composite psoriasis scoresin ABIN-1fl/fl CD11c-Cre mice compared with control chi-mera (Fig. 3A). Histologic examination of skin sections fromthese mice revealed epidermal hyperplasia, hypogranulosis,hyperkeratosis, and parakeratosis with neutrophils—all ste-reotypical histologic findings of human psoriasis—in ABIN-1fl/fl CD11c-Cre mice but not in control mice (Fig. 3B–G).Treatment of mice with a topical emollient as control did notlead to significant clinical responses. Hence, ABIN-1 expres-sion in DCs prevents susceptibility to experimental psoriasis.IMQ-induced psoriasis involves IL-23–dependent produc-
tion of IL-17 (24). We thus measured the levels of inflam-matory cytokines produced by ABIN-12/2 BMDCs comparedwith control BMDCs in response to IMQ. IMQ stimulatedhigher levels of IL-23, IL-6, IL-12p70, and TNF secretionfrom ABIN-12/2 BMDCs compared with wild-type BMDCs,whereas IL-12p40 levels were similar (Fig. 3H). We next testedthe induction of IL-17 expression in IMQ-treated mice.Whereas the total numbers of T cells in skin-draining lymphnodes were similar in ABIN-1fl/fl CD11c-Cre and ABIN-1+/+
CD11c-Cre chimera, increased numbers and percentages ofCD4+ Th17 cells were observed in ABIN-1fl/fl CD11c-Cremice (Fig. 3I). Many IL-17–producing T cells in IMQ-treatedmice are epidermal TCRg/d+ T cells (28). Consistent with thisnotion, increased percentages and numbers of TCRg/d+ T cellswere noted in draining lymph nodes from ABIN-1fl/fl CD11c-Cre mice (Fig. 3I). In contrast, analyses of the skin-draininglymph nodes from IMQ-treated ABIN-1fl/fl CD11c-Cre miceshowed approximately normal Th1 (IFN-g+) cell numbers andno significant numbers of Th2 (IL-4+) cells (Fig. 3I and data notshown). Finally, consistent with the role of IL-17 in supportingneutrophil recruitment, ABIN-1fl/fl CD11c-Cre mice containedincreased epidermal neutrophilic microabscesses (Fig. 3G). Thus,ABIN-1 expression in DCs restricts IL-23 secretion, Th17 celldifferentiation, neutrophilic inflammation, and psoriatic lesionsafter IMQ treatment.To determine whether ABIN-1–dependent regulation of
MyD88-dependent signals in DCs was integral to diseasepathogenesis, we tested the IMQ responses of chimera gen-erated from ABIN-1fl/flMyD88fl/fl CD11c-Cre compoundmutant and control hematopoietic stem cells. Double mutantABIN-1fl/flMyD88fl/fl CD11c-Cre mice exhibited much lesspsoriasis than did ABIN-1fl/fl CD11c-Cre mice (Fig. 4A).Indeed, ABIN-1fl/flMyD88fl/fl CD11c-Cre mice exhibitedsimilar clinical responses to MyD88fl/fl CD11c-Cre and wild-type chimera (Fig. 4A, Supplemental Fig. 2E). Histologicalstudies confirmed the reduced inflammation observed inABIN-1fl/flMyD88fl/fl CD11c-Cre mice compared withABIN-1fl/fl CD11c-Cre mice (Fig. 4B). Thus, ABIN-1–de-pendent regulation of MyD88-dependent signals in DCsregulates susceptibility to experimental psoriasis.Our findings indicate that ABIN-1 restricts MyD88-
dependent signals in DCs. ABIN-1 expression in DCsrestricts TLR-induced NF-kB and JNK signals, thereby lim-iting DC expression of IL-23 and other cytokines. IL-23
supports the accumulation of IL-17– and IL-22–producingT cells. IL-17 induces epidermal neutrophil infiltration, andIL-22 alters keratinocyte proliferation and differentiation.Thus, exaggerated IL-23 expression likely leads to character-istic dermal lesions of psoriasis (29). Our studies mechanis-tically link ABIN-1, a major psoriasis susceptibility gene, withIL-23a and IL-23R, two other major psoriasis susceptibilitygenes. This linkage suggests that ABIN-1 and IL-23–de-pendent inflammation may be part of a common dominantpathophysiological pathway leading to psoriasis. These cellu-lar and molecular insights into how ABIN-1 prevents psoriasisprovide mechanistic insights for the genetic suggestions aboutpsoriasis pathophysiology. Moreover, mice bearing ABIN-1mutations should be extremely valuable models for studyingpsoriasis pathophysiology and treatment.
AcknowledgmentsWe thank Sandra Huling and Ivy Hsieh of the University of California, San
Francisco Veterans Affairs Medical Center Pathology Core for excellent assis-
tance with histological studies.
DisclosuresThe authors have no financial conflicts of interest.
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