IL-22-producing Th22 cells play a protective role in CVB3-induced chronic myocarditis and dilated cardiomyopathy by inhibiting myocardial fibrosis
© Guo et al.; licensee BioMed Central. 2014
Received: 1 August 2014
Accepted: 16 December 2014
Published: 30 December 2014
A new subset of T helper (Th) cells, named IL-22-producing Th22 cells, was identified recently. Th22 cells have been implicated in immunity and inflammation. However, the role of these cells in the progression from acute viral myocarditis (AVMC) to dilated cardiomyopathy (DCM) and myocardial fibrosis remains unknown.
BALB/c mice were repeatedly i.p. infected with Coxsackie virus B3 (CVB3) to establish models of AVMC, chronic myocarditis and DCM. On week 2, 12 and 24 post initial injection, the percentage of splenic Th22 cells, the levels of plasma IL-22, cardiac IL-22 receptor (IL-22R) expression, and indicators of myocardial fibrosis were measured. Further, mice with AVMC and chronic myocarditis were treated with an anti-IL-22 neutralizing antibody (Ab). The collagen volume fraction (CVF), the percentage of splenic Th22 cells, plasma IL-22 levels, cardiac IL-22R expression and indicators of myocardial fibrosis were then monitored.
Compared to control mice at the same time points, AVMC, chronic myocarditis and DCM mice have higher percentage of splenic Th22 cells, higher plasma IL-22 levels, increased cardiac IL-22R, as well as increased collagen typeI-A1 (COL1-A1), collagen type III-A1 (COL3-A1) and matrix metalloproteinase-9 (MMP9) expression. However, the expression of tissue inhibitor of metalloproteinase-1(TIMP-1) was decreased. Treatment of AVMC and chronic myocarditis mice with an anti-IL-22 Ab decreased the survival rate and exacerbated myocardial fibrosis. The percentage of splenic Th22 cells, plasma IL-22 levels and cardiac IL-22R expression also decreased in anti-IL-22 Ab treatment group as compared to IgG and PBS treated groups of AVMC and chronic myocarditis mice. Moreover, increased expression of COL1-A1, COL3-A1, MMP9 but decreased expression of TIMP-1 were observed in anti-IL-22 Ab mouse group.
Th22 cells play an important role in the pathogenesis of CVB3-induced mouse chronic myocarditis and DCM. IL-22 is a myocardium-protective cytokine by inhibiting myocardial fibrosis. Therefore, Th 22 cells may be considered as potential therapeutic targets for DCM.
Viral myocarditis (VMC) is a common cardiac disease, characterized by myocardial inflammation due to virus infection. It was confirmed that the persistence of viral infection exists in some individuals with chronic myocarditis and dilated cardiomyopathy (DCM). Some patients with VMC may progress to chronic myocarditis and DCM, a terminal condition of heart failure and heart transplantation .
Emerging evidence has demonstrated that myocardial fibrosis is a major determinant in the development from VMC to DCM -. But the mechanism of myocardial fibrosis in disease procession has not been elucidated. It has been reported that T helper (Th) 1- and Th17-cell mediated autoimmune destruction may play an important role in myocardial fibrosis in which VMC progresses to DCM. However, Th1 and Th17 cell subsets may not fully explain the disease mechanism, because results from clinical trial and animal experiments concerning these T cell subsets were inconsistent -.
Th22 cells are a subset of CD4+ effector T cells that primarily secrete IL-22. These cells do not express IL-17, IL-4, or IFN-γ ,. IL-22 exerts its effect through IL-22R, which is a heterodimeric transmembrane receptor complex consisting of IL-22R1 and IL-10R2 . Th22 cells play a key role in autoimmune tissue injury, including organ-specific autoimmunity . Our previous studies have found that CVB3-induced AVMC mice have higher number of IL-22-producing Th22 cells and IL-22 shows critical anti-inflammatory and antiviral activity in disease development .
However, the role of Th22 cells and the mechanism of myocardial fibrosis in the course from AVMC to DCM are not clear. Therefore, our present study attempted to detect the percentage of Th22 cells, plasma IL-22 levels and cardiac IL-22R expression at stage of chronic myocarditis and DCM. We further explored the effect of neutralizing anti-IL-22 antibody (Ab) on myocardial fibrosis. Our study provided new insights into the role of Th22 cells in chronic myocarditis and DCM.
Evaluation of the severity of AVMC, chronic myocarditis and DCM
Exacerbation of myocardial fibrosis from AVMC to DCM
Increased proportions of splenic Th22, plasma IL-22 levels and myocardial IL-22R expression in AVMC, chronic myocarditis and DCM mice
Neutralization of IL-22 exacerbated the severity of AVMC and chronic myocarditis and the procession to DCM
Neutralization of IL-22 decreased the percentage of splenic Th22 cells, plasma IL-22 levels and cardiac IL-22R expression
Neutralization of IL-22 exacerbated myocardial fibrosis
VMC is a common cardiac disease and some patients with VMC may progress to chronic myocarditis and DCM, with a terminal condition of heart failure requiring heart transplantation. The main characteristic of DCM is extensive myocardial fibrosis, due to cardiomyocyte death and accumulation of extracellular matrix (ECM) protein. The main collagens in ECM are type I (50–85%) and type III (10–45%) collagens . We observed that the degree of myocardial fibrosis gradually increased with the progression from AVMC to DCM, accompanied by up-regulation of COL1-A1 and COLA3-A1. The role of MMP9 in infectious and autoimmune diseases was not clear, research with inconsistent reports -. TIMPs are inhibitors of MMPs, which disturb the pathological consequences through MMPs . The MMP/TIMP-1 ratio is correlated to the heart injury. Our data showed increased MMP9 level, MMP9/TIMP-1 ratio and decreased TIMP-1 level in AVMC, chronic myocarditis and DCM mice. Up-regulation of MMP9, MMP9/TIMP-1 ratio and down-regulation of TIMP-1 were more significant after neutralizing IL-22, associated with myocardial fibrosis exacerbation. Therefore, MMP-9 may act as a damaging factor in the pathogenesis of DCM.
Growing evidence suggests that Th22 cells may play an important role in autoimmune disease such as systemic lupus erythematosus , oral and cutaneous Lichen Planus lesions , neuromyelitis optica, multiple sclerosis , psoriasis, psoriatic arthritis , and IgA nephropathy , as well as infectious disease including chronic HIV infection  and hepatitis ,. Recently, Th22 cells have been implicated in endocrine and cardiovascular diseases, such as type 1 diabetes , type 2 diabetes and obesity , acute coronary syndrome , coxsackievirus B3 (CVB3)-induced acute viral myocarditis  and DCM .
Our previous study showed that Th22 cells and IL-22 may be a double-edged sword. Th22 cells and IL-22 have critical anti-inflammatory and antiviral effect in CVB3-induced mouse AVMC . However, in IL-17A-deficient mice, IL-22 exacerbates CVB3-induced acute viral myocarditis . Similar results were reported  concerning either protective and proinflammatory effects of Th22 cells. Our data showed that, compared with control mice at the same time points, the percentage of the pure Th22 cell, plasma IL-22 and cardiac protein expression of IL-22R were up-regulated in AVMC, chronic myocarditis and DCM groups. Then the myocardial fibrosis increased and survival rate decreased in mice after neutralizing IL-22, accompanied by a decline in Th22 cell number, reduced IL-22, diminished IL-22R expression and increased indicators of myocardial fibrosis such as COL1-A1, COL3-A1, MMP9. Moreover, the severity of myocardial fibrosis in chronic myocarditis after neutralizing IL-22 is similar to DCM. These results revealed that neutralization of IL-22 exacerbated the severity of AVMC and chronic myocarditis, aggravated myocardial fibrosis and accelerated the procession of DCM. Thus, Th22 cells and IL-22 play a protective role in DCM by inhibiting myocardial fibrosis and act as therapeutic targets.
However, there are several limitations in our study. First of all, the small number of mice, especially survival mice after neutralization of IL-22, may have a causal effect on outcome. In addition, the circulating IL-22 in vivo may not be completely antagonized using the injected dose of anti-IL-22 Ab. Other cells such as NKT, Th17 etc. can produce IL-22, those cells may interfere with the study of th22 cell function. As part of future efforts, it will be important to increase the number of mice and eliminate circulating IL-22 as much as possible, knockout mice may be used if necessary to confirm our results further.
In summary, our study demonstrated that the up-regulations of IL-22-producing Th22 cells may play an important part in the pathogenesis of CVB3-induced mice chronic myocarditis and DCM by inhibiting myocardial fibrosis. IL-22 may serve as a myocardium-protective cytokine by means of decreasing COL1-A1, COL3-A1, MMP9 and increasing TIMP-1. In order to explore the therapeutic potential of Th22 cells in the progression from AVMC to DCM, future studies, which focus on regulating the downstream pathways of Th22 cells would be more promising.
Pathogen-free male BALB/c mice aged 4 week were purchased from the Guangdong Medical Laboratory Animal Centre, Foshan, China (Certificate No. SCXK (Yue) 2008–0002). All animals were kept in pathogen-free mouse room in Experimental Animal Center of the Guangxi Medical University, Nanning, China. All experiments were carried out in accordance with protocols approved by Guangxi Medical University Animal Ethics Committee.
CVB3 (Nancy strain, from Institute of immunology of Guangxi Medical University) was maintained by passaging through Hep-2 cells. Virus titer was determined by plaque-forming unit (PFU) assay at 1 × 108. CVB3 was diluted in phosphate-buffered saline (PBS) (Solarbio Science &Technology Co, Ltd, Beijing, China).
Induction of AVMC, chronic myocarditis and DCM
BALB/c mice were infected by intraperitoneal injection (i.p) of 100 μl PBS containing approximately ~ 106 PFUs of the virus for establishing AVMC. For chronic myocarditis and DMC, BALB/c mice were infected by the same dose of virus on day 0. Subsequently the virus was injected once every 4 weeks in increments of 10 μl in a total of three doses for establishing chronic myocarditis and six doses for establishing DCM.
One hundred BALB/c mice were randomly divided into four groups: 1) 20 in the AVMC group; 2) 20 in chronic myocarditis group; 3) 20 in DCM group; and 4) the rest mice as a PBS injection control group (n = 30). All surviving animals with AVMC and 10 control mice were sacrificed by the end of week 2 after infection. In chronic myocarditis and DCM, surviving animals and 10 control mice were sacrificed by the end of week 12 and 24, respectively. Heart and spleen were removed aseptically and blood was harvested to obtain plasma.
Neutralization of IL-22
A total of 60 mice infected with CVB3 were randomly divided into two groups: 1) week 2 group, in which all surviving animals were sacrificed on day 14 after CVB3 infection, and 2) week 12 group, on day 84 after treatment with CVB3, all surviving mice were sacrificed. Each mouse group was separated into three subgroups: i.p. administration of anti-IL-22 Ab (50 μg per mouse every 4 weeks, at day 0, day 28 and day 56, n = 10, anti-IL-22Ab subgroup); normal IgG control (50 μg per mouse; n = 10, IgG control subgroup) and PBS (50 μg per mouse; n = 10, PBS subgroup). Anti-IL-22 Ab and normal IgG were from R&D Systems, Inc. Minneapolis. The survival rates of each mouse group were recorded and plasma, hearts and spleens of surviving mice were harvested on day 14 in week 2 group and day 84 in week 12 group.
The left-ventricular tissues of the mouse heart were fixed in 10% formalin, then were embedded in paraffin. The tissues were incised into 5-μm sections along the length of the heart, and stained with H&E (hematoxylin and eosin) or Masson’s Trichrome. Histopathological changes were observed (Olympus BX53 Microscope, Tokyo, Japan).
Spleens from mice were collected to prepare a single-cell suspension. The cells were resuspended in RPMI 1640 (Wisent, Nanjing, China) medium with 10% Superior Placental Bovine Serum (sijiqing, Hangzhou, China) and stimulated with phorbol myristate acetate (PMA, 25 ng/ml, Sigma-Aldrich, USA) and ionomycin (1 μg/ml, Sigma-Aldrich, USA) in the presence of GolgiPlug (1ul/106 cells, BD Biosciences, USA) at 37°C, 5% CO2 in 24-well culture plate. After 5 h incubation, the cells were harvested and stained with PERCP-CY5.5 conjugated anti-mouse CD4 (PERCP-CY5.5-CD4, BD Biosciences). The cells were stained intracellularly with anti–IL-22, −IL-17, or –IFN-γ mAb conjugated with PE, APC, or FITC after fixation and permeabilization (BD Biosciences, eBioscience), then analyzed on a FACS-Calibur flow cytometer (BD Bioscience). FlowJo 7.6 (Treestar, USA) was used for data acquisition. Th22 cells were defined as IL-22 + IL-17-IFN-γ-CD4 +.
Rabbit polyclonal antibodies against mouse IL-22R (Bioss, Beijing, China) were used as primary antibodies at a 1: 200 dilution. The heart sections were stained by using streptavidin-biotin complex kit (Boster, Wuhan, China). After the sections were rehydrated, endogenous peroxidase activity was blocked with 3% hydrogen peroxide for 10 min at room temperature. The sections were then incubated in 5% bovine serum albumin for 20 min followed by in the primary antibody at 4°C for 24 h. The sections were incubated with streptavidin-biotin complex for 20 min and visualized with 3, 3-diaminobenzidine (Boster, Wuhan, China) under a light microscope. Non-immune goat serum was used as a control. IL-22R in the cytoplasm and cytomembrane of myocardium was evaluated semi-quantitatively using Image-Pro Plus Version 6.0 (Media Cybernetics, Bethesda, MD). 5 fields from each slice were randomly selected by two pathologists to measure integrated optical density (IOD).
Sequences of primers for real-time RT-PCR
Sequence (5’ ~ 3’)
Plasma cytokine content was determined using enzyme-linked immunosorbent assays. IL-22 was measured by the Mouse IL-22 Platinum Enzyme linked immunosorbent assay (ELISA) (eBioscience, BMS6022, USA). The levels of COL1-A1, TIMP-1 and MMP9 in mice were also determined by ELISA (Cusabio Biotech, China and Boster, China). The sensitivity of ELISA kits for IL-22, COL1-A1, TIMP-1 and MMP9 was 5, 78, 39 and 5 pg/ml, respectively, and no cross-reactivity was detected. All samples were measured in triplicate.
Data were expressed as the means ± standard deviation (SD). Statistical analyses were performed with one-way ANOVA. Correlations were determined by Spearman rank correlation coefficients. Kaplan-Meier survival curve was used to estimate the survival rate of mice and the log-rank test was used to assess the difference of the survival rate among mouse groups. All statistical analyses of data were performed using SPSS 17.0 (IBM, USA). Differences at p < 0.05 among the means were deemed to be statistically significant.
This work is supported by the grants from the National Natural Science Foundation of China (Nos. 81160032 and 81260045). We thank Dr. Lan Jiao, Huang Qiguang for technical assistances. We are grateful to Dr. Ji Ming Wang of the NCI, NIH, for editing of the manuscript.
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