IL-22-producing Th22 cells play a protective role in CVB3-induced chronic myocarditis and dilated cardiomyopathy by inhibiting myocardial fibrosis

Abstract

BackgroundA 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.MethodsBALB/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.ResultsCompared 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.ConclusionsTh22 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.

Altered mTOR and Beclin-1 mediated autophagic activation during right ventricular remodeling in monocrotaline-induced pulmonary hypertension

“…Tissues were subjected to sectioning (5 μm thickness) as well as hematoxylin and eosin (H&E) stain. Cardiac fibrosis was analyzed by staining RV tissue sections with Masson’s trichrome stain, and collagen volume fraction (CVF) was assessed as previously described [35]. Cardiomyocyte cross-sectional area was assessed by staining RV tissues with wheat germ agglutinin conjugated to Alexa Fluor® 488 dye (WGA, Invitrogen, Carlsbad, CA, USA) and counterstained for nuclei with 4, 6-diamidino-2-phenylindole (DAPI, Sigma-Aldrich, St. Louis, MO, USA).…”

Fibrosis Related Inflammatory Mediators: Role of the IL‐10 Cytokine Family

“…However, our knowledge is limited, and elevated level of IL-22 was demonstrated in the heart of mice with dilated cardiomyopathy and cardiac fibrosis. Treatment of mice with IL-22-specific antibody decreased the survival rate of the animals and exacerbated myocardial fibrosis suggesting the cardioprotective role of IL-22 through the inhibition of myocardial fibrosis [ 84 ].…”

IL‐22 produced by Th22 cells aggravates atherosclerosis development in ApoE−/− mice by enhancing DC‐induced Th17 cell proliferation

“…In addition, percentage of Th22 cells (CD4 + IFN‐γ − IL‐17 − IL‐22 + cells) was notably increased in acute myocardial infarction (2.23 ± 1.58%) and unstable angina (2.09 ± 0.60%) patients compared with stable angina patients (0.93 ± 0.26%) or healthy controls (0.84 ± 0.18%) . In contrast, the results of dilated cardiomyopathy (DCM) studies showed that Th22 cells may inhibit myocardial fibrosis, indicating that these cells may have a protective role in DCM . Thus, the role of Th22 cells in cardiovascular disease (CVD) needs to be further explored.…”