Interleukin-33 Receptor (ST2) Deficiency Improves the Outcome of Staphylococcus aureus-Induced Septic Arthritis

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.

The Lipid Mediator Resolvin D1 Reduces the Skin Inflammation and Oxidative Stress Induced by UV Irradiation in Hairless Mice

“…Cytokines such as IL-1β, IL-6, IL-33, and TNF-α are involved in many cellular and tissue alterations in UVB irradiation, which include the recruitment of neutrophils that produce ROS and MMP-9, thus, with implications on inflammation and tissue remodeling (Garcia et al, 1999 ; Witko-Sarsat et al, 2000 ; Robinson et al, 2004 ; Verri et al, 2006 ; Walz and Cayabyab, 2017 ). Cytokines also affect vascular permeability, inducing tissue edema (Joosten et al, 2006 ; Zarpelon et al, 2013 ; Staurengo-Ferrari et al, 2018 ). Other cytokines such as TGF-β and IL-10 limit inflammation and orchestrate tissue repair (Verri et al, 2006 ; Penn et al, 2012 ).…”

“…For instance, UV induces the IL-33 expression by keratinocytes and dermal fibroblasts, which recruit dermal mast cells and skin-infiltrating neutrophils (Byrne et al, 2011 ). IL-33, IL-1β, and TNF-α also contribute to the development of inflammatory edema (Joosten et al, 2006 ; Zarpelon et al, 2013 ; Staurengo-Ferrari et al, 2018 ). Therefore, these data on inhibitory effect of RvD1 over UVB irradiation-induced pro-inflammatory cytokine production contribute to explain, at least in part, the reduction of skin inflammation (edema, mast cell counts, neutrophil recruitment, MMP-9 activity and collagen degradation).…”

The Role of ST2 Receptor in the Regulation of Brucella abortus Oral Infection

“…In ST2 knockout mice, MPO and EPO were decreased after infection when compared to WT animals, which might contribute to the initial resistance profile exhibited by these mice, since there are less infected granulocytes that can carry the pathogen to spread into other host cells and organs. The absence of ST2 increased the bactericidal activity of neutrophils and macrophages against Staphylococcus aureus in a sepsis model [63], by increasing the production of nitric oxide of these cells. Thus, we sought to investigate whether, in an in vitro scenario, macrophages would show higher production of NO against Brucella infection.…”

The IL-33/ST2 Axis in Immune Responses Against Parasitic Disease: Potential Therapeutic Applications

“…IL-33/ST2 signaling has further been demonstrated to be of positive benefit in innate immunity at the site of the skin, where its expression activates downstream production of antimicrobial reactive oxygen and nitrogen species (Li et al, 2014). Pathologies associated with bacterial infections including pediatric asthma and Staphylococcus aureus induced septic arthritis, however, have been found to respond negatively with expression of IL-33 or ST2 (Hentschke et al, 2017;Staurengo-Ferrari et al, 2018). IL-33 involved mechanisms have also been demonstrated to show divergent roles in the resistance to different fungal infections, where it has been noted to be protective in the context of candidiasis but hinders clearance of Aspergillus fumigatus infection (Park et al, 2016;Garth et al, 2017).…”