Activated human valvular interstitial cells sustain interleukin-17 production to recruit neutrophils in infective endocarditis
Journal
Infection and Immunity
Journal Volume
83
Journal Issue
6
Pages
2202-2212
Date Issued
2015
Author(s)
Yeh, Chiou-Yueh
Jung, Chiau-Jing
Chiu, Yen-Ling
Yang, Chia-Ju
Abstract
The mechanisms that underlie valvular inflammation in streptococcus-induced infective endocarditis (IE) remain unclear. We previously demonstrated that streptococcal glucosyltransferases (GTFs) can activate human heart valvular interstitial cells (VIC) to secrete interleukin-6 (IL-6), a cytokine involved in T helper 17 (Th17) cell differentiation. Here, we tested the hypothesis that activated VIC can enhance neutrophil infiltration through sustained IL-17 production, leading to valvular damage. To monitor cytokine and chemokine production, leukocyte recruitment, and the induction or expansion of CD4+ CD45RA- CD25- CCR6+ Th17 cells, primary human VIC were cultured in vitro and activated by GTFs. Serum cytokine levels were measured using an enzyme-linked immunosorbent assay (ELISA), and neutrophils and Th17 cells were detected by immunohistochemistry in infected valves from patients with IE. The expression of IL-21, IL-23, IL-17, and retinoic acid receptor-related orphan receptor C (Rorc) was upregulated in GTF-activated VIC, which may enhance the proliferation of memory Th17 cells in an IL-6-dependent manner. Many chemokines, including chemokine (C-X-C motif) ligand 1 (CXCL1), were upregulated in GTF-activated VIC, which might recruit neutrophils and CD4+ T cells. Moreover, CXCL1 production in VIC was induced in a dose-dependent manner by IL-17 to enhance neutrophil chemotaxis. CXCL1-expressing VIC and infiltrating neutrophils could be detected in infected valves, and serum concentrations of IL-17, IL-21, and IL-23 were increased in patients with IE compared to healthy donors. Furthermore, elevated serum IL-21 levels have been significantly associated with severe valvular damage, including rupture of chordae tendineae, in IE patients. Our findings suggest that VIC are activated by bacterial modulins to recruit neutrophils and that such activities might be further enhanced by the production of Th17-associated cytokines. Together, these factors can amplify the release of neutrophilic contents in situ, which might lead to severe valvular damage. ? 2015, American Society for Microbiology.
SDGs
Other Subjects
CD45RA antigen; chemokine receptor CCR6; CXCL1 chemokine; glucosyltransferase; interleukin 17; interleukin 21; interleukin 23; interleukin 6; retinoid related orphan receptor gamma; glucosyltransferase; interleukin 17; interleukin 21; interleukin 23; interleukin 6; interleukin derivative; leukocyte antigen; membrane protein; adolescent; adult; aged; Article; bacterial endocarditis; CD25+ T lymphocyte; CD4+ T lymphocyte; cell activation; cell expansion; cell proliferation; child; clinical article; controlled study; cytokine production; enzyme activation; enzyme linked immunosorbent assay; female; human; human cell; human cell culture; human tissue; immunohistochemistry; in vitro study; leukocyte; leukocyte migration; Leydig cell; male; memory T lymphocyte; neutrophil; neutrophil chemotaxis; priority journal; protein blood level; protein expression; school child; Th17 cell; upregulation; valvular heart disease; valvular interstitial cell; bacterial endocarditis; cell culture; cell motion; cytology; enzymology; gene expression regulation; genetics; heart valve; inflammation; metabolism; middle aged; neutrophil; physiology; preschool child; Streptococcus; Streptococcus infection; very elderly; Adult; Aged; Aged, 80 and over; Antigens, CD; Cell Movement; Cells, Cultured; Child; Child, Preschool; Endocarditis, Bacterial; Female; Gene Expression Regulation; Glucosyltransferases; Heart Valves; Humans; Inflammation; Interleukin-17; Interleukin-23; Interleukin-6; Interleukins; Male; Membrane Proteins; Middle Aged; Neutrophils; Streptococcal Infections; Streptococcus; Th17 Cells
Publisher
American Society for Microbiology
Type
journal article