Interleukin-17A during local and systemic Staphylococcus aureus-induced arthritis in mice

Abstract

Staphylococcus aureus is one of the dominant pathogens that induce septic arthritis in immunocompromised hosts, e.g., patients suffering from rheumatoid arthritis treated with immunosuppressive drugs. S. aureus-induced arthritis leads to severe joint destruction and high mortality despite antibiotic treatment. Recently, interleukin-17A (IL-17A) has been discovered to be an important mediator of aseptic arthritis both in mice and humans, but its function in S. aureus-induced arthritis is largely unknown. Here, we investigated the role of IL-17A in host defense against arthritis following systemic and local S. aureus infection in vivo. IL-17A knockout mice and wild-type mice were inoculated systemically (intravenously) or locally (intra-articularly) with S. aureus. During systemic infection, IL-17A knockout mice lost significantly more weight than the wild-type mice did, but no differences were found in the mortality rate. The absence of IL-17A had no impact on clinical arthritis development but led to increased histopathological erosivity late during systemic S. aureus infection. Bacterial clearance in kidneys was increased in IL-17A knockout mice compared to the level in wild-type mice only 1 day after bacterial inoculation. During systemic S. aureus infection, serum IL-17F protein levels and mRNA levels in the lymph nodes were elevated in the IL-17A knockout mice compared to the level in wild-type mice. In contrast to systemic infection, the IL-17A knockout mice had increased synovitis and erosions and locally decreased clearance of bacteria 3 days after local bacterial inoculation. On the basis of these findings, we suggest that IL-17A is more important in local host defense than in systemic host defense against S. aureus-induced arthritis.

FIG. 1.

Weight change, mortality, and arthritis in C57BL/6 mice during systemic S. aureus infection. Clinical findings in IL-17A knockout C57BL/6 mice (open circles) and wild-type C57BL/6 mice (closed squares) during systemic S. aureus infection are shown. (A to C) Weight change as a percentage of initial weight (A), absolute weight change (in grams) (B), and mortality (C). (D and E) Clinical severity (D) and frequency of arthritis (E) during systemic S. aureus infection. (F) Histology of joints from mice 3, 7, and 13 days after intravenous S. aureus inoculation. S, synovitis; E, erosions. In panels A to E, the values are means ± standard errors of the means (SEMs) (error bars). In panel F, each symbol shows the histological index for one mouse. Horizontal bars represent median values. Values that are significantly different in the wild-type mice and IL-17A knockout mice are indicated by the P values (P = 0.01, P = 0.02, or P = 0.04).

FIG. 2.

Weight change, mortality, arthritis IL-17F protein levels, and number of peripheral neutrophils in BALB/c mice during systemic S. aureus infection. Clinical findings in IL-17A knockout BALB/c mice (open circles) and wild-type BALB/c mice (closed squares) during systemic S. aureus infection are shown. (A and B) Weight change as a percentage of initial weight (A) and mortality (B). (C) Clinical severity of arthritis. In panels A to C, the means ± SEMs (error bars) are shown. (D and E) Serum protein levels of IL-17F (D) and number of neutrophils (10⁶) in blood (E). The values that are significantly different (P = 0.01) in wild-type and IL-17A knockout mice are indicated. In panels D and E, each symbol shows the value for one mouse. Horizontal bars represent median values.

FIG. 3.

IL-17F and G-CSF expression and neutrophil count during systemic S. aureus infection. (A to D) IL-17F mRNA in lymph nodes (A), IL-17F protein levels in serum (B), G-CSF protein levels in serum (C), and number of neutrophils (10⁶) in blood (D) from IL-17A knockout mice (open circles) and wild-type mice (closed squares) at the indicated day after systemic S. aureus infection. Each symbol shows the value for one mouse. Horizontal bars represent median values. Values that are significantly different in the wild-type and IL-17A knockout mice are indicated (e.g., P = 0.03, P = 0.02, etc.).

FIG. 4.

IL-6 and IFN-γ protein levels during systemic S. aureus infection. IL-6 (A) and IFN-γ (B) protein levels in serum from IL-17A knockout mice (open circles) and wild-type mice (closed squares) at the indicated day after systemic S. aureus infection. Horizontal bars represent median values. The values that are significantly different in the wild-type and IL-17A knockout mice are indicated (P = 0.002 and P = 0.03).

FIG. 5.

Histology from joints 3 days after intra-articular inoculation of S. aureus. (A) Severity of synovitis and joint erosivity. Each symbol shows the value for one mouse. The bars represent median values. Wild-type mice (closed squares) and IL-17A knockout mice (open circles) were examined. The values that are significantly different in the wild-type and IL-17A knockout mice are indicated (P = 0.02 and P = 0.049). (B and C) Histopathological pictures from the knee joint of a wild-type mouse (B) and an IL-17A knockout mouse (C). The black arrowheads indicate areas with cartilage and bone destruction. Abbreviations: S, synovia; M, meniscus; C, cartilage; B, bone (B and C).

FIG. 6.

Bacterial growth and neutrophils in the synovial membrane 3 days after intra-articular S. aureus inoculation. Bacterial growth (A), typical gating for neutrophils defined as Gr-1-positive and major histocompatibility complex (MHC) class II-negative cells in the synovial membrane (B), absolute numbers of neutrophils (C), and MPO activity (D) in the synovial membrane. In panels A, C, and D, wild-type (Wt) mice (closed squares) and IL-17A knockout (ko) mice (open circles) were compared. In panels A and D, each symbol shows the value for one mouse, and the bars represent median values. In panel C, the data are shown as box-and-whisker plots.