Abstract
The ST2 receptor is a member of the Toll/IL-1R superfamily and interleukin-33 (IL-33) is its agonist. Recently, it has been demonstrated that IL-33/ST2 axis plays key roles in inflammation and immune mediated diseases. Here, we investigated the effect of ST2 deficiency in Staphylococcus aureus-induced septic arthritis physiopathology. Synovial fluid samples from septic arthritis and osteoarthritis individuals were assessed regarding IL-33 and soluble (s) ST2 levels. The IL-33 levels in samples from synovial fluid were significantly increased, whereas no sST2 levels were detected in patients with septic arthritis when compared with osteoarthritis individuals. The intra-articular injection of 1 × 107 colony-forming unity/10 μl of S. aureus American Type Culture Collection 6538 in wild-type (WT) mice induced IL-33 and sST2 production with a profile resembling the observation in the synovial fluid of septic arthritis patients. Data using WT, and ST2 deficient (−/−) and interferon-γ (IFN-γ)−/− mice showed that ST2 deficiency shifts the immune balance toward a type 1 immune response that contributes to eliminating the infection due to enhanced microbicide effect via NO production by neutrophils and macrophages. In fact, the treatment of ST2−/− bone marrow-derived macrophage cells with anti-IFN-γ abrogates the beneficial phenotype in the absence of ST2, which confirms that ST2 deficiency leads to IFN-γ expression and boosts the bacterial killing activity of macrophages against S. aureus. In agreement, WT cells achieved similar immune response to ST2 deficiency by IFN-γ treatment. The present results unveil a previously unrecognized beneficial effect of ST2 deficiency in S. aureus-induced septic arthritis.
Highlights
Interleukin-33 (IL-33) is a member of the IL-1 cytokine family that can act either as a chromatin-associated nuclear factor or as a classic cytokine [1, 2]
The i.a. injection of S. aureus induced the increase of IL-33 levels (Figure 1C) and decreased of sST2 levels (Figure 1D) in the knee joints that lasted for 28 days compared with day 0
In view of Th1 and Th2 response have long been balancing one another [52] and that there are similar evidences regarding the relationship between Th1 and Th17 [52, 53], we found a lower number of gated IL-17+CD4+T cells in lymph nodes (LNs) from ST2−/− mice compared with WT at 7th and 14th day post-infection (Figures S2D,E in Supplementary Material), which lined up with IL-17 amounts in infected joint tissue at all time points evaluated (7–28 days post-infection, Figure S2F in Supplementary Material), raising the possibility that ST2−/− mice use Th1 cells in lieu of Th17 cells to drive the immune response against S. aureus-induced septic arthritis
Summary
Interleukin-33 (IL-33) is a member of the IL-1 cytokine family that can act either as a chromatin-associated nuclear factor or as a classic cytokine [1, 2]. The transmembrane form of ST2, encoded by the ST2 gene is expressed by cells including activated Th2 cells [5], mast cells [6], and ILC2 [7]. Antibodies targeting ST2, ST2-Fc fusion proteins or ST2 deficient mice contributed to demonstrate that the lack of IL-33/ST2 signaling favors the expansion of Th1 cells and inhibits Th2 cell-mediated immune responses [5, 8,9,10,11]. IL-33/ST2 signaling has emerging pleiotropic properties, including type 1 and 3 immunity and regulatory patterns [4, 12]. Endothelial cells and fibroblasts constitutively express high levels of IL-33 mRNA and protein, indicating that they are a key source of IL-33 in the inflamed synovium [11, 16]. IL-33 and ST2 are expressed by joint cells in inflammatory conditions
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