Abstract
Mycoplasma arthritidis causes arthritis in specific mouse strains. M. arthritidis mitogen (MAM), a superantigen produced by M. arthritidis, activates T cells by forming a complex between the major histocompatability complex II on antigen presenting cells and the T cell receptor on CD4+ T lymphocytes. The MAM superantigen is also known to interact with Toll-like receptors (TLR) 2 and 4. Hepcidin, an iron regulator protein, is upregulated by TLR4, IL-6, and IL-1. In this study, we evaluated serum hepcidin, transferrin saturation, ferritin, IL-6, IL-1, and hemoglobin levels in M. arthritidis injected C3H/HeJ (TLR2+/+, TLR4-/-) mice and C3H/HeSnJ (TLR2+/+, TLR4+/+) mice over a 21 day period. C3H/HeJ mice have a defective TLR4 and an inability to produce IL-6. We also measured arthritis severity in these mice and the amount of hepcidin transcripts produced by the liver and spleen. C3H/HeJ mice developed a more severe arthritis than that of C3H/HeSnJ mice. Both mice had an increase in serum hepcidin within three days after infection. Hepcidin levels were greater in C3H/HeJ mice despite a nonfunctioning TLR4 and low serum levels of IL-6. Splenic hepcidin production in C3H/HeJ mice was delayed compared to C3H/HeSnJ mice. Unlike C3H/HeSnJ mice, C3H/HeJ mice did not develop a significant rise in serum IL-6 levels but did develop a significant increase in IL-1β during the first ten days after injection. Both mice had an increase in serum ferritin but a decrease in serum transferrin saturation. In conclusion, serum hepcidin regulation in C3H/HeJ mice does not appear to be solely dependent upon TLR4 or IL-6.
Highlights
Mycoplasma arthritidis (M. arthritidis) is a rodent pathogen that causes arthritis and a toxic shock-like syndrome in C3H mice
We found that hepcidin levels were increased in both mouse strains and hepcidin regulation was independent of TLR4 and IL-6
Serum hepcidin increased with arthritis severity in both mouse strains within the first three days of infection
Summary
Mycoplasma arthritidis (M. arthritidis) is a rodent pathogen that causes arthritis and a toxic shock-like syndrome in C3H mice. M. arthritidis injected mice have been used as a mouse model of human inflammatory arthritis for more than 30 years. MAM is a unique superantigen in that it interacts with Toll like receptor (TLR) 4 and 2 found on cells of the innate immune system (page number not for citation purposes). Compared to C3H/ HeSnJ mice, C3H/HeJ mice have a mutant lpsd gene that leads to a hypofunctional TLR4 [3]. Macrophages from C3H/HeJ mice upregulate the number of cell surface TLR2 when exposed to the MAM superantigen [2]. C3H/HeJ injected mice have a type 1 cytokine profile (IL2, interferon-γ, and tumor necrosis factor α) compared to inoculated C3H/HeSnJ mice that have a type 2 cytokine profile (IL-4, IL-6, and IL-10) [3]
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