IL-33/ST2 Axis Plays a Protective Effect in Streptococcus pyogenes Infection through Strengthening of the Innate Immunity.
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ABSTRACT:
SUBMITTER: Kuo CF
PROVIDER: S-EPMC8509005 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Interleukin 33 (IL-33) is highly expressed in barrier sites, acting via the suppression of tumorigenicity 2 receptor (ST2). IL-33/ST2 axis has long been known to play a pivotal role in immunity and cell homeostasis by promoting wound healing and tissue repair. However, it is also involved in the loss of balance between extensive inflammation and tissue regeneration lead to remodeling, the hallmark of fibrosis. The aim of the current review is to critically evaluate the available evidence regarding the role of the IL-33/ST2 axis in organ fibrosis. The role of the axis in tissue remodeling is better understood considering its crucial role reported in organ development and regeneration. Generally, the IL-33/ST2 signaling pathway has mainly anti-inflammatory/anti-proliferative effects; however, chronic tissue injury is responsible for pro-fibrogenetic responses. Regarding pulmonary fibrosis mature IL-33 enhances pro-fibrogenic type 2 cytokine production in an ST2- and macrophage-dependent manner, while full-length IL-33 is also implicated in the pulmonary fibrotic process in an ST2-independent, Th2-independent fashion. In liver fibrosis, evidence indicate that when acute and massive liver damage occurs, the release of IL-33 might act as an activator of tissue-protective mechanisms, while in cases of chronic injury IL-33 plays the role of a hepatic fibrotic factor. IL-33 signaling has also been involved in the pathogenesis of acute and chronic pancreatitis. Moreover, IL-33 could be used as an early marker for ulcer-associated activated fibroblasts and myofibroblast trans-differentiation; thus one cannot rule out its potential role in inflammatory bowel disease-associated fibrosis. Similarly, the upregulation of the IL-33/ST2 axismay contribute to tubular cell injury and fibrosis via epithelial to mesenchymal transition (EMT) of various cell types in the kidneys. Of note, IL-33 exerts a cardioprotective role via ST2 signaling, while soluble ST2 has been demonstrated as a marker of myocardial fibrosis. Finally, IL-33 is a crucial cytokine in skin pathology responsible for abnormal fibroblast proliferation, leukocyte infiltration and morphologic differentiation of human endothelial cells. Overall, emerging data support a novel contribution of the IL-33/ST2 pathway in tissue fibrosis and highlight the significant role of the Th2 pattern of immune response in the pathophysiology of organ fibrosis.
| S-EPMC6207585 | biostudies-other
Project description:Innate immunity has been extended to respond environmental pathogen other than microbial components. Here we explore a novel pollen/TLR4 innate immunity in allergic inflammation. In experimental allergic conjunctivitis induced by short ragweed (SRW) pollen, typical allergic signs, stimulated IL-33/ST2 signaling and overproduced Th2 cytokine were observed in ocular surface, cervical lymph nodes and isolated CD4+ T cells of BALB/c mice. These clinical, cellular and molecular changes were significantly reduced/eliminated in TLR4 deficient (Tlr4-d) or MyD88 knockout (MyD88-/-) mice. Aqueous SRW extract (SRWe) directly stimulated IL-33 mRNA and protein expression by corneal epithelium and conjunctiva in wild type, but not in Tlr4-d or MyD88-/- mice with topical challenge. Furthermore, SRWe-stimulated IL-33 production was blocked by TLR4 antibody and NF-kB inhibitor in mouse and human corneal epithelial cells. These findings for the first time uncovered a novel mechanism by which SRW pollen initiates TLR4-dependent IL-33/ST2 signaling that triggers Th2-dominant allergic inflammation.
| S-EPMC5087075 | biostudies-literature
Project description:A bacterium's ability to acquire nutrients from its host during infection is an essential component of pathogenesis. For the Gram-positive pathogen Streptococcus pyogenes, catabolism of the amino acid arginine via the arginine deiminase (ADI) pathway supplements energy production and provides protection against acid stress in vitro. Its expression is enhanced in murine models of infection, suggesting an important role in vivo. To gain insight into the function of the ADI pathway in pathogenesis, the virulence of mutants defective in each of its enzymes was examined. Mutants unable to use arginine (ΔArcA) or citrulline (ΔArcB) were attenuated for carriage in a murine model of asymptomatic mucosal colonization. However, in a murine model of inflammatory infection of cutaneous tissue, the ΔArcA mutant was attenuated but the ΔArcB mutant was hyperattenuated, revealing an unexpected tissue-specific role for citrulline metabolism in pathogenesis. When mice defective for the arginine-dependent production of nitric oxide (iNOS(-/-)) were infected with the ΔArcA mutant, cutaneous virulence was rescued, demonstrating that the ability of S. pyogenes to utilize arginine was dispensable in the absence of nitric oxide-mediated innate immunity. This work demonstrates the importance of arginine and citrulline catabolism and suggests a novel mechanism of virulence by which S. pyogenes uses its metabolism to modulate innate immunity through depletion of an essential host nutrient.
| S-EPMC3911826 | biostudies-literature
Project description:Mast cells (MC) are potent innate immune cells that accumulate in chronically inflamed tissues. MC express the IL-33 receptor IL-1 receptor-related protein ST2 at high level, and this IL-1 family cytokine both activates MC directly and primes them to respond to other proinflammatory signals. Whether IL-33 and ST2 play a role in MC survival remains to be defined. In skin-derived human MC, we found that IL-33 attenuated MC apoptosis without altering proliferation, an effect mediated principally through the antiapoptotic molecule B-cell lymphoma-X large (BCLXL). Murine MC demonstrated a similar mechanism, dependent entirely on ST2. In line with these observations, St2(-/-) mice exhibited reduced numbers of tissue MC in inflamed arthritic joints, in helminth-infected intestine, and in normal peritoneum. To confirm an MC-intrinsic role for ST2 in vivo, we performed peritoneal transfer of WT and St2(-/-) MC. In St2(-/-) hosts treated with IL-33 and in WT hosts subjected to thioglycollate peritonitis, WT MC displayed a clear survival advantage over coengrafted St2(-/-) MC. IL-33 blockade specifically attenuated this survival advantage, confirming IL-33 as the relevant ST2 ligand mediating MC survival in vivo. Together, these data reveal a cell-intrinsic role for the IL-33/ST2 axis in the regulation of apoptosis in MC, identifying thereby a previously unappreciated pathway supporting expansion of the MC population with inflammation.
| S-EPMC4104908 | biostudies-other
Project description:Collectins are C-type lectins that are involved in innate immunity as pattern recognition molecules. Recently, collectin kidney 1 (CL-K1) has been discovered, and in vitro studies have shown that CL-K1 binds to microbes and activates the lectin complement pathway. However, in vivo functions of CL-K1 against microbes have not been elucidated. To investigate the biological functions of CL-K1, we generated CL-K1 knockout (CL-K1-/-) mice and then performed a Streptococcus pneumoniae infection analysis. First, we found that recombinant human CL-K1 bound to S. pneumoniae in a calcium-dependent manner, and induced complement activation. CL-K1-/- mice sera formed less C3 deposition on S. pneumoniae. Furthermore, immunofluorescence analysis in the wild-type (WT) mice demonstrated that CL-K1 and C3 were localized on S. pneumoniae in infected lungs. CL-K1-/- mice revealed decreased phagocytosis of S. pneumoniae. Consequently, less S. pneumoniae clearance was observed in their lungs. CL-K1-/- mice showed severe pulmonary inflammation and weight loss in comparison with WT mice. Finally, the decreased clearance and severe pulmonary inflammation caused by S. pneumoniae infection might cause higher CL-K1-/- mice lethality. Our results suggest that CL-K1 might play an important role in host protection against S. pneumoniae infection through the activation of the lectin complement pathway.
| S-EPMC6738814 | biostudies-other
Project description:Streptococcus pyogenes is an important human pathogen that causes invasive diseases such as necrotizing fasciitis, sepsis, and streptococcal toxic shock syndrome. We investigated the function of a major cysteine protease from S. pyogenes that affects the amount of C1-esterase inhibitor (C1-INH) and other complement factors and aimed to elucidate the mechanism involved in occurrence of streptococcal toxic shock syndrome from the aspect of the complement system. First, we revealed that culture supernatant of a given S. pyogenes strain and recombinant SpeB degraded the C1-INH. Then, we determined the N-terminal sequence of the C1-INH fragment degraded by recombinant SpeB. Interestingly, the region containing one of the identified cleavage sites is not present in patients with C1-INH deficiency. Scanning electron microscopy of the speB mutant incubated in human serum showed the abnormal superficial architecture and irregular oval structure. Furthermore, unlike the wild-type strain, that mutant strain showed lower survival capacity than normal as compared with heat-inactivated serum, whereas it had a significantly higher survival rate in serum without the C1-INH than in normal serum. Also, SpeB degraded multiple complement factors and the membrane attack complex. Flow cytometric analyses revealed deposition of C9, one of the components of membrane the attack complex, in greater amounts on the surface of the speB mutant, whereas lower amounts of C9 were bound to the wild-type strain surface. These results suggest that SpeB can interrupt the human complement system via degrading the C1-INH, thus enabling S. pyogenes to evade eradication in a hostile environment.
| S-EPMC3668742 | biostudies-literature
Project description:ObjectiveThe IL-33/ST2 axis has been extensively investigated in type 2 eosinophilic inflammation. Here, we aimed to investigate the role of the IL-33/ST2 axis in neutrophil-dominant allergic airway inflammation.MethodsHouse-dust mite (HDM) extract and lipopolysaccharide (LPS) were administered to establish a murine model of neutrophil-dominant allergic airway inflammation. The formation of neutrophilic extracellular traps (NETs) in the lung tissues was demonstrated by immunofluorescence imaging. Mature IL-33 in bronchoalveolar lavage fluid (BALF) was detected by Western blotting. The neutrophilic chemokine KC produced by bone marrow-derived macrophages (BMDMs) or primary alveolar epithelial cells was measured with a commercial ELISA kit.ResultsIn the present study, we observed neutrophilic inflammation and tight junction damage in the lungs of mice sensitised with HDM and LPS. Furthermore, sensitisation with HDM and LPS resulted in the formation of NETs, accompanied by increased levels of mature IL-33 in the BALF. Moreover, LPS damaged the epithelial tight junction protein occludin directly or indirectly by inducing NET formation. Surprisingly, IL-33 deficiency augmented neutrophilia and epithelial barrier injury in the lungs of mice after sensitisation with HDM and LPS. Similarly, the absence of ST2 exacerbated the neutrophilic inflammatory response, decreased the expression of occludin and exacerbated the severity of neutrophil-dominant allergic airway inflammation in an HDM/LPS-induced mouse model. Mechanistically, BMDMs and alveolar epithelial cells from IL-33- or ST2-deficient mice tended to produce higher levels of the neutrophilic chemokine KC.ConclusionsThese results demonstrated that the IL-33/ST2 axis may play a protective role in neutrophil-dominant allergic airway inflammation.
| S-EPMC8207976 | biostudies-literature
Project description:Interleukin-33 (IL-33), an important member of the IL-1 family, plays a pivotal role in regulating immune responses via combining with its receptor suppression of tumorigenicity 2 (ST2). We have already known IL-33/ST2 axis participates in the pathogenesis of various diseases, including liver diseases, renal diseases, and neurological diseases. Recently, emerging studies are indicating that IL-33/ST2 is also involved in a wide range of ocular diseases, such as allergic eye disease, keratitis and corneal regeneration, dry eye disease, uveitis, vitreoretinal diseases, and neuromyelitis optica spectrum disorder. In this review, we will summarize and discuss the current understanding about the functional roles of IL-33/ST2 in eyes, with an attempt to explore the possible study perspectives and therapeutic alternatives in the future.
| S-EPMC7450335 | biostudies-literature
Project description:Il1rl1 (also known as ST2) is a member of the IL-1 superfamily, and its only known ligand is IL-33. ST2 exists in two forms as splice variants: a soluble form (sST2), which acts as a decoy receptor, sequesters free IL-33, and does not signal, and a membrane-bound form (ST2), which activates the MyD88/NF-κB signaling pathway to enhance mast cell, Th2, regulatory T cell (Treg), and innate lymphoid cell type 2 functions. sST2 levels are increased in patients with active inflammatory bowel disease, acute cardiac and small bowel transplant allograft rejection, colon and gastric cancers, gut mucosal damage during viral infection, pulmonary disease, heart disease, and graft-versus-host disease. Recently, sST2 has been shown to be secreted by intestinal pro-inflammatory T cells during gut inflammation; on the contrary, protective ST2-expressing Tregs are decreased, implicating that ST2/IL-33 signaling may play an important role in intestinal disease. This review will focus on what is known on its signaling during various inflammatory disease states and highlight potential avenues to intervene in ST2/IL-33 signaling as treatment options.
| S-EPMC5402045 | biostudies-literature
Project description:Streptococcus pyogenes is one of the main pathogenic bacteria that causes disease in humans. It is reported that over 18 million cases of S. pyogenes disease occurred in the world, and more than 500,000 deaths occur annually worldwide. An effective vaccine is widely regarded as the most reliable way to control and prevent streptococcal infections. However, there is currently no approved vaccine for S. pyogenes. In this study, we evaluated the potential of lipoprotein FtsB as a new vaccine candidate to prevent S. pyogenes infection. Mice vaccinated with purified FtsB protein elicited high titers of IgG, IgG1 and IgG2a antibodies in mouse serum. Vaccinated with FtsB can reduce bacterial systemic dissemination in the blood, heart, and spleen and reduce organ damage in the mouse bacteremia model. In addition, active immunization with FtsB protected against streptococcal abscess formation. Furthermore, immunization with FtsB was efficient in inducing a mixed cellular immune response and promoting the maturation of dendritic cells in mice. The lipoprotein HtsA was served as a positive control because it has been reported to protect mice from S. pyogenes infection in both active and passive immunization. These findings demonstrated that lipoprotein FtsB may serve as a candidate vaccine for the prevention of S. pyogenes infection.
| S-EPMC9396372 | biostudies-literature