Pathogenic effect of interleukin-17A in induction of Sjögren's syndrome-like disease using adenovirus-mediated gene transfer
© Nguyen et al.; licensee BioMed Central Ltd. 2010
Received: 20 September 2010
Accepted: 23 December 2010
Published: 23 December 2010
Sjögren's syndrome (SS) involves a chronic, progressive inflammation primarily of the salivary and lacrimal glands leading to decreased levels of saliva and tears resulting in dry mouth and dry eye diseases. Seminal findings regarding TH17 cell populations that secrete predominantly interleukin (IL)-17A have been shown to play an important role in an increasing number of autoimmune diseases, including SS. In the present study, we investigated the function of IL-17A on the development and onset of SS.
Adenovirus serotype 5 (Ad5) vectors expressing either IL-17A or LacZ were infused via retrograde cannulation into the salivary glands of C57BL/6J mice between 6 and 8 weeks of age or between 15 and 17 weeks of age. The mice were characterized for SS phenotypes.
Disease profiling indicated that SS-non-susceptible C57BL/6J mice whose salivary glands received the Ad5-IL17A vector developed a SS-like disease profile, including the appearance of lymphocytic foci, increased cytokine levels, changes in antinuclear antibody profiles, and temporal loss of saliva flow.
Induction of SS pathology by IL-17A in SS-non-susceptible mice strongly suggests that IL-17A is an important inflammatory cytokine in salivary gland dysfunction. Thus, localized anti-IL17 therapy may be effective in preventing glandular dysfunction.
Sjögren's syndrome (SS) is a chronic, systemic autoimmune disease characterized most notably by development of dry eyes and dry mouth manifestations, indicative of secretory dysfunction of the lacrimal and salivary glands [1–3]. Although the etiology of SS remains unknown, intensive studies of an ever-expanding number of animal models is beginning to unravel the genetic, molecular and immunological basis for this disease . Previous studies have implicated critical roles for both interferon-γ (IFN-γ) and interleukin (IL)-4 in the development and onset of SS-like disease in NOD/LtJ and C57BL/6.NOD-Aec1Aec2 mice [4, 5], strongly suggesting involvement of TH1 and TH2 cell populations, respectively. While IFN-γ regulates cell-mediated immunity through activation of macrophages, NK cells and CD8+ T cells, this cytokine appears to predispose these SS-susceptible mice by retarding salivary gland organogenesis, especially proliferation of acinar tissue . This delay in acinar cell maturation has been postulated to prevent expression of cellular antigens at the critical time of self-tolerance, resulting in inefficient clonal deletion of acinar tissue-reactive T cells. In contrast to the role of IFN-γ both prior to and during development of SS, IL-4 appears to be essential during development of adaptive immunity and subsequent onset of glandular dysfunction. Specifically, IL-4 was shown to be necessary for proper isotypic switching, regulating B lymphocyte synthesis of pathogenic IgG1 anti-muscarinic acetylcholine type III receptor (M3R) autoantibodies [6, 7].
Although these earlier studies have implicated both TH1 and TH2 cell-associated functions in the development and onset of clinical SS, recent identification of the CD4+ TH17 memory cells within the lymphocytic focus (LF) of lacrimal and salivary glands of SSs C57BL/6.NOD-Aec1Aec2 mice, as well as minor salivary glands of human SS patients, greatly expands the potential complexity in deciphering the autoimmune response underlying SS [8, 9]. The TH17 cell population, while clearly a subset of CD4+ memory effector T cells, appears to be distinct from, and unrelated to, either the TH1 or TH2 cell lineages [10–14]. TH17 effector cells secrete at least one of the six cytokines belonging to the IL-17 family, that is, IL-17A, IL-17B, IL-17C, IL-17D, IL-25 and/or IL-17F; however, IL-17A, the signature cytokine, has received the greatest attention in studies of autoimmune diseases . The IL-17 cytokines are potent pro-inflammatory molecules, actively involved in tissue inflammation via induction of pro-inflammatory cytokine and chemokine expressions . In addition, IL-17 is involved in the mobilization, maturation and migration of neutrophils via the release of IL-8 at the site of injury . Interestingly, IL-17A is known to regulate Foxp3+ TReg cells and vice versa .
While TH17 cells have been implicated in several autoimmune diseases (for example, Crohn's disease [19, 20], experimental autoimmune encephalomyelitis (EAE) , collagen-induced arthritis (CIA) , SS  and others [2, 3]), this characteristic may require signaling from TH1 cells already present in the lesion . In any event, recent observational studies in SS patients and animal models of primary SS have identified the presence of IL-17A and its activating cytokine IL-23 in the lymphocytic infiltrates of the exocrine glands, as well as higher levels of circulating IL-17A in both sera and saliva , raising the question of the importance of IL-17 in SS. Thus, the goals of the present study were to determine whether IL-17A can directly influence the pathology leading to the onset of SS-like disease by administrating exogenous IL-17A to the salivary glands at specific time points.
Materials and methods
SS non-susceptible C57BL/6J mice were bred and maintained under specific pathogen-free conditions. The animals were maintained on a 12-hr light-dark schedule and provided food and acidified water ad libitum. At times indicated in the text, mice were euthanized by cervical dislocation following deep anesthetization with isoflurane, after which organs were freshly explanted for analyses. Both the breeding and use of these animals for the present studies were approved by the University of Florida's IACUC and IBC. Salivary glands of mice were cannulated with mouse IL-17A-expressing Ad5-IL17A vector using retrograde injections at either 7 weeks (wks) of age (n = 11) or 16 wks of age (n = 8). In addition, mice at 6 wks (n = 4) and 15 wks (n = 4) were randomly selected and used as pre-treated or baseline analysis. Age- and sex-matched control C57BL/6J mice (n = 10 per age group) received the Ad5-LacZ control vector using the same protocols.
Production of Ad5-LacZ and Ad5-IL17A vectors
The recombinant adenovirus vectors used in this study were generously provided by Dr. Jay K. Kolls (Children's Hospital of Pittsburgh, Pittsburgh, PA, USA). These vectors are based on the first generation adenovirus serotype 5 (Ad5) and shown to produce their appropriate and functional mouse IL- 17A and LacZ products [22–24]. To obtain sufficient viral vectors for the present studies, each recombinant vector was amplified in HEK293 cells, purified by two rounds of CsCl gradient centrifugation, then dialyzed against 100 mM Tris-HCl (pH 7.4), 10 mM MgCl2 and 10% (v/v) glycerol, as described elsewhere .
Retrograde salivary gland cannulation of Ad5-LacZ or Ad5-IL17A vectors
Previous studies have demonstrated that retrograde salivary gland cannulation is an effective method to direct local gene expression in the salivary glands [26–28]. In brief, prior to cannulation, each mouse was anesthetized with a ketamine:xylazine mixture (100 mg/mL, 1 mL/kg body weight; Fort Dodge Animal Health, Fort Dodge, IA, USA) and xylazine (20 mg/mL, 0.7 mL/kg body weight; Phoenix Scientific, St. Joseph, MO, USA)) intramuscularly. Stretched PE-10 polyethylene tubes were inserted into each of the two openings of the salivary ducts. After securing the cannulas, the mouse received an intramuscular injection of atropine (1 mg/kg), followed 10 minutes later by a slow, steady injection of viral vector. Each salivary gland received 50 μl of vector solution containing 107 viral particles). The cannulas were removed five minutes later to ensure successful cannulation.
Measurement of saliva flow
To measure stimulated saliva flow, individual non-anesthetized mice were weighed and given an intraperitoneal injection of 100 μl of phosphate-buffered saline (PBS) containing isoproterenol (0.02 mg/ml) and pilocarpine (0.05 mg/ml). Saliva was collected for 10 minutes from the oral cavity of individual mice using a micropipette starting 1 minute after injection of the secretagogue. The volume of each saliva sample was measured. Prior to vector cannulation and again at each time-point designated in the text, saliva and sera were collected from each mouse. Samples were stored at -80°C until analyzed.
Determination of cytokines levels
Measurements of IL-6 and IL-17A cytokine levels in sera samples were performed by an independent contractor (Millipore, Billerica, MA, USA) using Luminex® platform.
Intracellular cytokine staining and flow cytometric analysis
Spleens were freshly explanted, gently minced through stainless steel sieves, suspended in PBS and centrifuged (1,200 rpm for five minutes). Erythrocytes were lysed by seven-minute incubation in 0.84% NH4Cl. The resulting leukocyte suspensions were washed two times in PBS, counted and resuspended inculture media (RPMI 1640 medium, 10% FBS, 2 mM L-glutamine, 0.05 mM β-mercaptoethanol) at a density of 2 × 106 cells/ml. One million cells were pipetted to individual wells of a 24-well microtiter plate pre-coated with anti-CD3 (10 μg/ml) and anti-CD28 antibodies (2 μg/ml) for T cell activation. Cells were incubated for five hours with Leukocyte Activation Cocktail containing GolgiPlug (2 μl/ml). Collected cells were fixed and permeabilized using Cytofix/CytopermFixation/Permeabilization. Flow cytometric acquisition for intracellular staining was performed following staining with PE-Cy5-conjugated anti-mouse CD4, FITC-conjugated anti-IFN-γ and PE-conjugated anti-IL-17AA. The cells were counted on a FACSCalibur (BD, Franklin Lakes, NJ, USA) and analyzed by FCS Express (De Novo Software, Los Angeles, CA, USA).
Following euthanasia, whole salivary glands containing submandibular, sublingual, and parotid glands were surgically removed from each mouse and placed in 10% phosphate-buffered formalin for 24 hrs. Fixed tissues were embedded in paraffin and sectioned at 5 μm thickness. Paraffin-embedded sections were de-paraffinized by immersing in xylene, followed by dehydrating in ethanol. The tissue sections were prepared and stained with hematoxylin and eosin (H&E) dye. Stained sections were observed under a microscope for glandular structure and leukocyte infiltration determination. A double-blinded procedure was used to enumerate leukocytic infiltrations (lymphocytic foci) in the histological sections of salivary glands. Lymphocytic foci (LF) were defined as aggregates of >50 leukocytes quantified per each histological section. Calculations were based on one histological section per mouse.
Immunofluorescent staining for CD3+T cells and B220+B cells
Histological sections of salivary glands were incubated with rat anti-mouse B220 (BD Pharmingen, San Jose, CA, USA) and goat anti-mouse CD3 (Santa Cruz Biotechnology, Santa Cruz, CA, USA), followed by incubation with Texas Red-conjugated rabbit anti-rat IgG (Biomeda, Foster City, CA, USA) and FITC-conjugated rabbit anti-goat IgG (Sigma-Aldrich, St. Louis, MO, USA). The slides were mounted with DAPI-mounting medium (Vector Laboratories, Burlingame, CA, USA). Sections were observed at 200X magnification using a Zeiss Axiovert 200 M microscope.and images were obtained with AxioVs40 software (Ver. 18.104.22.168, Zeiss) (Carl Zeiss, Thornwood, NY, USA). Enumeration of B, T cells and total number of nuclei in the LF were performed using Mayachitra imago software (Mayachitra, Inc, Santa Barbara, CA, USA).
Immunohistochemical staining for IL17A in salivary glands
Immunohistochemical staining for IL17A were carried out as previously described . In brief, paraffin-embedded salivary glands were deparaffinized by immersion in xylene, followed by antigen retrieval with 10 mM citrate buffer, pH 6.0. Tissue sections were incubated overnight at 4°C with anti-IL-17A antibody (Santa Cruz Biotechnology). Isotype controls were done with rabbit IgG. The slides were incubated with biotinylated goat anti-rabbit IgG followed by horseradish peroxidase-conjugated strepavidin incubation using the Vectastain ABC kit. The staining was developed by using diaminobenzidine substrate (Vector Laboratories), and counterstaining was performed with hematoxylin. Sections were observed at 200X magnification using a Zeiss Axiovert 200 M microscope. And images were obtained with AxioVs40 software (Ver. 22.214.171.124, Zeiss) (Carl Zeiss). Enumeration of IL17A-positive cells was performed on the entire histological sections of the whole salivary glands using Mayachitra imago software (Mayachitra, Inc.), although lymphocytic infiltrations are normally seen only in the submandibular glands.
Detection of antinuclear antibodies (ANA) in the sera
ANA in the sera of mice were detected using HEp-2 ANA kit (INOVA Diagnostics, Inc., San Diego, CA, USA). All procedures were performed per manufacturer's instructions. In brief, HEp-2 fixed substrate slides were overlaid with appropriate mouse sera diluted 1:40, 1:80 and 1:160. Slides were incubated for one hour at room temperature in a humidified chamber. After three washes for five minutes with PBS, the substrate slides were covered with Alexa 488-conjugated goat anti-mouse IgG (H/L) (Invitrogen Inc, Carlsbad, CA, USA) diluted 1:100 for 45 minutes at room temperature. After three washes, fluorescence was detected by fluorescence microscopy at 200X magnification using a Zeiss Axiovert 200 M microscope and all images were obtained with AxioVs40 software with constant exposure of 0.3 seconds (Carl Zeiss). Negative controls are secondary antibody only and positive controls are standard serum with nuclear speckled pattern provided with the kits. Data presented in the results are from slides using 1:40 dilutions of sera from each experimental group.
Statistical evaluations were determined by using the Mann-Whitney U test generated by the GraphPad InStat software (GraphPad Software, La Jolla, CA, USA). The two-tailed P-value < 0.05 was considered significant.
Induction of IL-17A and IL-6 cytokine levels in sera following transduction with Ad5-IL17A vector
Adenoviral vectors have been reported to show peak gene expressions around Day 5 post-infusion and then persist for approximately two weeks . In the current study, immunohistochemical staining for the presence of LacZ protein in the infused salivary glands demonstrated that optimal transduction efficiency was approximately 26 ± 5% at two weeks post-infusion which decreased to 15 ± 3% by nine weeks post-infusion. The cells within the salivary glands positive for LacZ expression were predominantly ductal cells, as expected, and acinar cells (data not shown), indicating the virus was capable of passing through the ducts.
Increased numbers of IL-17A-producing CD4+ T cells in the spleens of Ad5-IL17A transduced mice
As mentioned previously, salivary glands were cannulated with Ad5-IL17A vector at either 7 wks or 16 wks of age. The time points chosen are based on extensive studies of the development and onset of disease in our C57BL/6.NOD-Aec1Aec2 mouse model of SS [1–3, 30, 31]. The two time points selected represent the innate and adaptive immune response phases, respectively, in the disease model, thus they were chosen to mimic these changes in the parental C57BL/6 mouse. Microarray analyses examined the temporal differential gene expression of salivary and lacrimal glands of C57BL/6 mice revealed gradual change in pathophysiological related genes from 16 to 20 wks of age, concomitantly, leukocyte infiltration in the exocrine glands is often observed at these ages [32, 33]. Thus, it is important to examine the role of IL17A in the development of SS prior and post to any pathophysiological changes.
Induction of SS immune-pathology in C57BL/6 mice following treatment with Ad5-IL17A vector
Quantification of lymphocytic foci (LF) in salivary glands
4 ± 1.32c
2 ± 0.83
Besides the number of LF detected in the salivary glands of the experimental animals, immunofluorescent staining to detect B and T cells revealed further differences in the cellular composition of the infiltrations between mice administered Ad5-IL17A at an early or late stage. At time of euthanasia, C57BL/6J mice treated with Ad5-IL17A vector at 7 wks of age generally exhibited smaller foci containing fewer IL-17 positive cells compared to mice receiving the vector at 16 wks of age (Figure 3c-f, i-l). Consistent with previous observation, the smaller foci in mice treated at 7 wks of age may have resulted from the longer duration of time after cannulation (19 wks) reflecting the decreases in IL-17A serum levels and IL-17A- positive cell numbers. Detailed examination of IL-17A-positive cells revealed that a majority of IL-17A cells are present in the LF and ductal cells with smaller percentage of positive cells found in the epithelium and acinar cells. Nevertheless, these data support the concept that formation and maintenance of LF are due, in part, to the expression levels of IL17A in the salivary glands.
Changes in ANA profiles following instillation of the Ad5-IL-17A vector
Induction of salivary gland dysfunction in C57BL/6J mice following cannulation with Ad5-IL17A vector
The TH17-derived IL-17A cytokine is a potent inflammatory cytokine that has been implicated in a growing list of autoimmune diseases, for example, multiple sclerosis, Crohn's disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, and SS, as well as autoimmunity in animal models . As the TH17/IL-17A system is considered to be an important factor in innate immunity that, in turn, regulates development of the adaptive immune response, it is not surprising that environmental microflora trigger IL-17A responses . The consequence of TH17/IL-17A activation includes, in addition to the production the IL-17A family of cytokines, the production of IL-21, IL-22, chemokines (MIP-2, CXCL1, CXCL2, CXCL5), and matrix metalloproteases (MMP3 and MMP13)  all actively involved in tissue inflammation. Interaction of the IL-17A with its receptors evokes activation of IL-8, resulting in recruitment of neutrophils to the site of injury. However, the relationship between such early innate/inflammatory events mediated by the TH17/IL-17A system and the role TH17 cells play in subsequent autoimmunity remains unknown, especially in light of the multiple functions now associated with the TH17 cell populations. Thus, in the present study, we have attempted to elucidate the importance of the cytokine IL-17A per se in the development of SS and whether its function may be dependent on when it is expressed.
Results in which SS-non-susceptible C57BL/6J mice were cannulated with the Ad5-IL17A vector revealed that increased IL-17A expression could induce several pathological features of SS, irrespective of whether the mice received the vector at 7 or 16 wks of age, two time points corresponding to innate and adaptive immune responses in SS-susceptible C57BL/6.NOD-Aec1Aec2 mice. This was noted by decreases in saliva production compared to control vector, elevated production of specific pro-inflammatory cytokines detected in sera, changes in the weak cytoplasmic/nuclear ANA patterns to nuclear specked staining on HEp2 cells and increased numbers of LF and IL17A positive cells present in the salivary glands at time of euthanasia. Interestingly, mice received Ad5-IL17A at 7 wks of age showed a slight recovery of saliva secretion at 7 wks of treatment in contrast to mice received Ad5-IL17A at 16 wks of age. This observation might be supported by the differential immunological or biological response of mice at different ages and the effect of Ad5-IL17A exerted on the mice.
Previous studies have indicated that genes placed within Ad5 vectors are generally expressed transiently and locally restricted (that is, 7 to 14 days) . The present study demonstrates that a rapid and significant increase in the levels of plasma IL-17A was affected at 12 days post-cannulation by the Ad5-IL17A transgene vector. Interestingly, this systemic increase in IL17 cytokine levels correlated with significant increases in splenic IL-17A secreting CD4+T cells that persisted at least 19 wks for mice treated at 7 wks of age and 11 wks for mice treated at 16 wks of age. These observations indicated that the Ad5 vector effect was longer than anticipated. Whether this effect might be due to an indirect secondary effect of the Ad5-IL17 vector is unknown. In addition, the systemic increase in IL17A production by local treatment of Ad5-IL17A presented in this study is consistent with previous studies by Bruce Baum's laboratory [35–38]. Adesanya et al.  has demonstrated that acinar cells can be punctured by retrograde salivary gland cannulation at a certain vector dosage. The injured acinar cells, which have compromised mucosal barrier integrity, allow for leakage of the vector systemically. Further studies by Kagami et al.  and He et al.  provided evidence that ductal cannulation of salivary glands can also have systemic effects due to the secretory nature of the salivary glands which are well endowed with protein synthesis organelles and secretory machinery.
Nevertheless, these observations are consistent with the concept that SS develops along specific biological processes in a sequential fashion and interference with this process alters development of disease [1–3]. Therefore, this study clearly indicates the pathogenic nature of IL-17A in inducing SS-like phenotypes when cannulated in the salivary glands.
Previous data have shown that lymphocytic infiltrates in the salivary glands secreting IL-17A and its related cytokines are more important in local glandular destruction. Staining salivary glands for IL-17A revealed that C57BL/6J mice receiving Ad5-IL17A vector not only expressed significant levels of IL-17A, but that IL-17A levels correlated with recruitment of inflammatory cells, specifically B and T cells, to the glands. This observation is important in light of the recent study suggesting IL-17A is a critical factor in the adaptive immune response by inducing the formation of germinal centers for the production of autoreactive antibodies . Autoantibodies represent a major component in the onset of SS, thus the changes in the ANA profiles observed with sera of C57BL/6J mice cannulated with the Ad5-IL17A vector indicate that IL-17A affects even the B cell compartment in SS-non-susceptible mice. The presence of LF and loss of saliva secretion raises an interesting question about the possible role of IL-17A in B cell activation. As BAFF is capable of inducing TH17 cell differentiation in addition to regulating B cell activation , the possible role of BAFF and IL17A in this phenomenon needs to be better defined in SS pathogenesis.
The capability of IL-17A to induce features of SS in SS-non-susceptible mice demonstrates the major role this cytokine plays in the development, and possible onset, of the autoimmune process. How this one cytokine affects the various features of autoimmunity, and at what level or time point, will require additional studies. More importantly, the study demonstrates that IL-17A might be a potential therapeutic target for SS.
adenovirus serotype 5
B cell activating factor
chemokine (C-X-C motif) ligand
experimental autoimmune encephalomyelitis
macrophage inflammatory protein-2
The authors would like to thank Dr. Jay K. Kolls and Dr. Julie Bindas (Children's Hospital of Pittsburgh) for generously providing the Ad5-LacZ and Ad5-IL17A vectors and Dr. Phil Cohen for his critical reading of the manuscript and helpful suggestions. We greatly appreciate the assistance of Dr. Craig Meyers and Dr. Nicholas Muzyczka for the use of the microscope. Publication of this article was funded in part by the University of Florida Open-Access publishing Fund.
Funding: This work was supported by PHS grants K99DE018958 (CQN) from NIDCR, R21AI081952 (ABP) from NIAID and funds from the Sjögren's Syndrome Foundation and Center for Orphan Autoimmune Disorders. HY and JAC were supported by an NIH, NIDCR intramural research grant.
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