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CXCR3 Blockade Inhibits T Cell Migration Into the Skin and Prevents Development of Alopecia Areata

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CXCR3 Blockade Inhibits T Cell Migration Into the Skin and Prevents Development of Alopecia Areata CXCR3 Blockade Inhibits T Cell Migration into the Skin and Prevents Development of Alopecia Areata This information is current as Zhenpeng Dai, Luzhou Xing, Jane Cerise, Eddy Hsi Chun of September 26, 2021. Wang, Ali Jabbari, Annemieke de Jong, Lynn Petukhova, Angela M. Christiano and Raphael Clynes J Immunol published online 13 July 2016 http://www.jimmunol.org/content/early/2016/07/13/jimmun ol.1501798 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2016/07/13/jimmunol.150179 Material 8.DCSupplemental http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 26, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published July 13, 2016, doi:10.4049/jimmunol.1501798 The Journal of Immunology CXCR3 Blockade Inhibits T Cell Migration into the Skin and Prevents Development of Alopecia Areata Zhenpeng Dai,* Luzhou Xing,† Jane Cerise,* Eddy Hsi Chun Wang,* Ali Jabbari,* Annemieke de Jong,* Lynn Petukhova,* Angela M. Christiano,*,‡,1 and Raphael Clynes*,1 Alopecia areata (AA) is an autoimmune disease of the hair follicle that results in hair loss of varying severity. Recently, we showed that IFN-g–producing NKG2D+CD8+ T cells actively infiltrate the hair follicle and are responsible for its destruction in C3H/HeJ AA mice. Our transcriptional profiling of human and mouse alopecic skin showed that the IFN pathway is the dominant signaling pathway involved in AA. We showed that IFN-inducible chemokines (CXCL9/10/11) are markedly upregulated in the skin of AA lesions, and further, that the IFN-inducible chemokine receptor, CXCR3, is upregulated on alopecic effector T cells. To demon- strate whether CXCL9/10/11 chemokines were required for development of AA, we treated mice with blocking Abs to CXCR3, which prevented the development of AA in the graft model, inhibiting the accumulation of NKG2D+CD8+ T cells in the skin and Downloaded from cutaneous lymph nodes. These data demonstrate proof of concept that interfering with the Tc1 response in AA via blockade of IFN-inducible chemokines can prevent the onset of AA. CXCR3 blockade could be approached clinically in human AA with either biologic or small-molecule inhibition, the latter being particularly intriguing as a topical therapeutic. The Journal of Immunol- ogy, 2016, 197: 000–000. http://www.jimmunol.org/ lopecia areata (AA) is one of the most prevalent auto- class I and II, leading to the loss of HF immune privilege and immune diseases with a lifetime incidence rate of 1.7% induction of autoimmune hair loss (9). Likewise, it has been A (1). AA is characterized by an extensive localized in- shown that blockade of the function of IFN-g inhibits the devel- flammatory T cell infiltrate around the hair follicle (HF) and focal, opment of alopecia in C3H/HeJ mice (5, 10). extensive, or complete hair loss in both males and females. The Recently, we determined that NK-type CD8+NKG2D+ T cells C3H/HeJ mouse model of AA, as well as the humanized rodent are the dominant immune effectors infiltrating the HF in both model with human alopecic skin explanted onto NOD/SCID mice, humans and C3H/HeJ mice with AA (5, 11). The signals that supported a T cell–dependent, autoimmune mechanism in which recruit autoreactive T cell migration into skin and HF leading to the breakdown of immune privilege is followed by an attack on AA are unknown. Leukocyte infiltration into inflammatory sites is by guest on September 26, 2021 anagen HF (2–4). We and others have observed that both human critical for the initiation and progression of a variety of inflam- AA patients and the C3H/HeJ mouse model of AA exhibit a matory disorders and is controlled via the activation and signaling striking IFN-g–specific Th1 cytokine signature in the skin (4–6). of specific cell-surface chemokine receptors (12–14). Chemokines IFN-g is prominently expressed in AA lesions and may contribute are a superfamily of chemotactic cytokines that play important to the collapse of HF immune privilege by upregulating MHC roles in the generation and maintenance of immune and inflamma- class I expression in the HF, which has been implicated in the tory responses. They are also involved in a wide range of disease pathogenesis of AA (7, 8). In C3H/HeJ mice, administration of processes, including infection, autoimmune, inflammatory, and ma- IFN-g has been shown to induce follicular expression of MHC lignant diseases (12–14). The CXCR3 receptor and its cognate ligands, CXCL9, CXCL10, *Department of Dermatology, College of Physicians and Surgeons, Columbia and CXCL11, have been implicated in directing a Th1 inflam- University, New York, NY 10032; †Department of Pathology, Columbia University, matory response (15–18). Recent studies support the notion that New York, NY 10032; and ‡Department of Genetics and Development, College of Physicians and Surgeons, Columbia University, New York, NY 10032 the CXCR3 receptor is an attractive therapeutic target for treating autoimmune diseases, such as rheumatoid arthritis (RA), vitiligo, 1A.M.C. and R.C. contributed equally to this work. and psoriasis (19–22). In humans, the efficiency of a blocking ORCIDs: 0000-0001-8568-1383 (J.C.); 0000-0001-7785-1442 (E.H.C.W.); 0000-0001-6707-6585 (A.d.J.); 0000-0002-7963-8482 (R.C.). CXCL10 Ab (MDX-1100) was reported in a phase 2 clinical trial Received for publication August 10, 2015. Accepted for publication June 7, 2016. for RA, and underscored the therapeutic potential blocking the CXCR3-CXCL10 axis in autoimmunity (23). This work was supported by National Institute of Arthritis and Musculoskeletal and Skin Diseases/National Institutes of Health Grants P30AR044535 and R01AR065963 We and others found that many of the upregulated genes in (to A.M.C.), Locks of Love, and a Research Award from the National Alopecia alopecic skin of both species were IFN-response genes, including Areata Foundation (to Z.D.). the IFN-inducible chemokines CXCL9-11 (5, 24). Chemokines Address correspondence and reprint requests to Dr. Angela M. Christiano, College of CXCL9 and CXCL10 are elevated in the serum of AA patients Physicians and Surgeons, Columbia University, Russ Berrie Medical Science Pavil- ion, Room 3-303, 1150 St. Nicholas Avenue, New York, NY 10032. E-mail address: (25). The marked upregulation of CXCR3 ligand expression, to- [email protected] gether with the increased number of CXCR3+ lymphocytes on The online version of this article contains supplemental material. infiltrating T cells, suggests further interrogation of the CXCR3 Abbreviations used in this article: AA, alopecia areata; DC, dendritic cell; HF, hair pathway in AA (25–27). To define the role of CXCR3 in AA follicle; LN, lymph node; qRT-PCR, quantitative RT-PCR; RA, rheumatoid arthritis; pathogenesis, we investigated chemokine expression in lesional SDLN, skin-draining lymph node. skin of patients with AA, as well as in C3H/HeJ mice, and studied Copyright Ó 2016 by The American Association of Immunologists, Inc. 0022-1767/16/$30.00 the consequences of CXCR3 blockade in mice with AA. www.jimmunol.org/cgi/doi/10.4049/jimmunol.1501798 2 CXCR3 PATHWAY IN ALOPECIA AREATA We demonstrate that CXCR3 ligands are highly expressed in Flow cytometric analysis was performed on BD LSRII flow cytometer (BD lesional skin of human AA patients and in C3H/HeJ mice with AA. Biosciences) and analyzed with FlowJo software (Tree Star). Viable cell Further, we found that blockade of the CXCR3-ligand interaction populations were gated based on forward and side scatters and by DAPI (BioLegend) staining. prevents the development of AA by markedly reducing the ac- cumulation of CD8+NKG2D+ T cell in lesional skin and inhibit- Immunohistochemistry and immunofluorescence staining + + ing expansion of CD8 NKG2D T cell in skin-draining lymph Immunofluorescence staining of tissue sections was performed as previously nodes (SDLNs). This study invites further investigation of CXCR3 described (5). The immunofluorescence staining of mouse MHC class I was blockade as a new therapeutic target for AA. performed using biotin-labeled mouse anti-H-2Kk,followedbyfluorochrome- conjugated streptavidin (Life Technologies). The endogenous biotin was blocked using a streptavidin/biotin blocking kit (Vector Laboratories). Im- Materials and Methods munohistochemical staining of formalin-fixed, paraffin-embedded tissue sec- Mice tions were performed using the microwave Ag retrieval method as previously described (5). In brief, human CD3 or CD8 Ag was retrieved with 10 mM of C3H/HeJ mice (The Jackson Laboratory) were maintained under specific citrate buffer (pH 6), and 1 mM of EDTA (pH 8) for human CD4 or CXCR3 pathogen-free conditions at the animal facility at the Columbia University Ag. For both frozen tissue and formalin-fixed, paraffin-embedded tissue sec- Medical Center. Transfer of AA was performed using grafted alopecic tion staining procedures, the individual primary Ab was used at optimal C3H/HeJ skin, as described previously (23). In brief, mice spontaneously concentrations for detection (final concentration ∼10 mg/ml), followed by affected with AA were euthanized, and full-thickness skin grafts of ∼2cm ImmPRESS HRP secondary Abs (Vector Laboratories). The detection of Ab in diameter were grafted onto 7- to 10-wk-old normal-haired female complexes was followed by incubation with ImmPACT NovaRED Peroxidase C3H/HeJ mice.
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