IL-33-ST2 signaling in fibro-adipogenic progenitors alleviates immobilization-induced muscle atrophy in mice.

BACKGROUND: The regenerative and adaptive capacity of skeletal muscles reduces with age, leading to severe disability and frailty in the elderly. Therefore, development of effective therapeutic interventions for muscle wasting is important both medically and socioeconomically. In the present study, we aimed to elucidate the potential contribution of fibro-adipogenic progenitors (FAPs), which are mesenchymal stem cells in skeletal muscles, to immobilization-induced muscle atrophy. METHODS: Young (2-3 months), adult (12-14 months), and aged (20-22 months) mice were used for analysis. Muscle atrophy was induced by immobilizing the hind limbs with a steel wire. FAPs were isolated from the hind limbs on days 0, 3, and 14 after immobilization for transcriptome analysis. The expression of ST2 and IL-33 in FAPs was evaluated by flow cytometry and immunostaining, respectively. To examine the role of IL-33-ST2 signaling in vivo, we intraperitoneally administered recombinant IL-33 or soluble ST2 (sST2) twice a week throughout the 2-week immobilization period. After 2-week immobilization, the tibialis anterior muscles were harvested and the cross-sectional area of muscle fibers was evaluated. RESULTS: The number of FAPs increased with the progression of muscle atrophy after immobilization in all age-groups. Transcriptome analysis of FAPs collected before and after immobilization revealed that Il33 and Il1rl1 transcripts, which encode the IL-33 receptor ST2, were transiently induced in young mice and, to a lesser extent, in aged mice. The number of FAPs positive for ST2 increased after immobilization in young mice. The number of ST2-positive FAPs also increased after immobilization in aged mice, but the difference from the baseline was not statistically significant. Immunostaining for IL-33 in the muscle sections revealed a significant increase in the number of FAPs expressing IL-33 after immobilization. Administration of recombinant IL-33 suppressed immobilization-induced muscle atrophy in aged mice but not in young mice. CONCLUSIONS: Our data reveal a previously unknown protective role of IL-33-ST2 signaling against immobilization-induced muscle atrophy in FAPs and suggest that IL-33-ST2 signaling is a potential new therapeutic target for alleviating disuse muscle atrophy, particularly in older adults.

The IL-33/ST2 axis is protective against acute inflammation during the course of periodontitis.

Periodontitis, which is induced by repeated bacterial invasion and the ensuing immune reactions that follow, is the leading cause of tooth loss. Periodontal tissue is comprised of four different components, each with potential role in pathogenesis, however, most studies on immune responses focus on gingival tissue. Here, we present a modified ligature-induced periodontitis model in male mice to analyze the pathogenesis, which captures the complexity of periodontal tissue. We find that the inflammatory response in the peri-root tissues and the expression of IL-6 and RANKL by Thy-1.2- fibroblasts/stromal cells are prominent throughout the bone destruction phase, and present already at an early stage. The initiation phase is characterized by high levels of ST2 (encoded by Il1rl1) expression in the peri-root tissue, suggesting that the IL-33/ST2 axis is involved in the pathogenesis. Both Il1rl1- and Il33-deficient mice exhibit exacerbated bone loss in the acute phase of periodontitis, along with macrophage polarization towards a classically activated phenotype and increased neutrophil infiltration, indicating a protective role of the IL-33/ST2 axis in acute inflammation. Thus, our findings highlight the hidden role of the peri-root tissue and simultaneously advance our understanding of the etiology of periodontitis via implicating the IL-33/ST2 axis.

Promoting (and targeting) alternative expression.

Lineage-specific effects of upstream promoters affect ST2 expression and effector function in TH1cells.

IL-33 Induces Cellular and Exosomal miR-146a Expression as a Feedback Inhibitor of Mast Cell Function.

IL-33 is an inflammatory cytokine that promotes allergic disease by activating group 2 innate lymphoid cells, Th2 cells, and mast cells. IL-33 is increased in asthmatics, and its blockade suppresses asthma-like inflammation in mouse models. Homeostatic control of IL-33 signaling is poorly understood. Because the IL-33 receptor, ST2, acts via cascades used by the TLR family, similar feedback mechanisms may exist. MicroRNA (miR)-146a is induced by LPS-mediated TLR4 signaling and serves as a feedback inhibitor. Therefore, we explored whether miR-146a has a role in IL-33 signaling. IL-33 induced cellular and exosomal miR-146a expression in mouse bone marrow-derived mast cells (BMMCs). BMMCs transfected with a miR-146a antagonist or derived from miR-146a knockout mice showed enhanced cytokine expression in response to IL-33, suggesting that miR-146a is a negative regulator of IL-33-ST2 signaling. In vivo, miR-146a expression in plasma exosomes was elevated after i.p. injection of IL-33 in wild-type but not mast cell-deficient KitW-sh/W-sh mice. Finally, KitW-sh/W-sh mice acutely reconstituted with miR-146a knockout BMMCs prior to IL-33 challenge had elevated plasma IL-6 levels compared with littermates receiving wild-type BMMCs. These results support the hypothesis that miR-146a is a feedback regulator of IL-33-mediated mast cell functions associated with allergic disease.

Nosocomial surveillance of multidrug-resistant Acinetobacter baumannii: a genomic epidemiological study.

Acinetobacter baumannii is a major opportunistic pathogen causing hospital-acquired infections, and it is imperative to comprehend its evolutionary and epidemiological dynamics in hospitals to prevent and control nosocomial transmission. Here, we present a comprehensive genomic epidemiological study involving the genomic sequencing and antibiotic resistance profiling of 634 A. baumannii strains isolated from seven intensive care units (ICUs) of a Chinese general hospital over 2 consecutive years. Our study reveals that ST2 is highly dominant (90.54%) in the ICUs, with 98.90% of the ST2 exhibiting multidrug resistant or extensively drug resistant. Phylogenetic analyses of newly sequenced genomes and public data suggest that nosocomial isolates originated outside the hospital but evolved inside. The major lineages appear to be stable, with 9 of the 28 identified nosocomial epidemic clones infecting over 60% of the affected patients. However, outbreaks of two highly evolved clones have been observed in different hospitals, suggesting significant inter-hospital transmission chains. By coupling patient medical records and genomic divergence of the ST2, we found that cross-ward patient transfer played a crucial role in pathogen's nosocomial transmission. Additionally, we identified 831 potential adaptive evolutionary loci and 44 associated genes by grouping and comparing the genomes of clones with different prevalence. Overall, our study provides a comprehensive and contemporary survey on the epidemiology and genomic evolution of A. baumannii in a large Chinese general hospital. These findings shed light on the nosocomial evolution and transmission of A. baumannii and offers valuable information for transmission prevention and antibiotic therapy.IMPORTANCEThis study delved into the genomic evolution and transmission of nosocomial Acinetobacter baumannii on a large scale, spanning both an extended time period and the largest sample size to date. Through molecular epidemiological investigations based on genomics, we can directly trace the origin of the pathogen, detecting and monitoring outbreaks of infectious diseases in a timely manner, and ensuring public health safety. In addition, this study also collects a large amount of genomic and antibiotic resistance detection data, which is helpful for phenotype prediction based on genomic sequencing. It enables patients to receive personalized antibiotic treatment quickly, helps doctors select antibiotics more accurately, and contributes to reducing the use of antibiotics and lowering the risk of antibiotic resistance development.

Recovery and genetic characterization of clinically-relevant ST2 carbapenem-resistant Acinetobacter baumannii isolates from untreated hospital sewage in Zhejiang Province, China.

The global transmission of carbapenem-resistant Acinetobacter baumannii (CRAB) poses a significant and grave threat to human health. To investigate the potential relationship between hospital sewage and the transmission of CRAB within healthcare facilities, isolates of Acinetobacter spp. obtained from untreated hospital sewage samples were subjected to antimicrobial susceptibility tests, genome sequencing, and bioinformatic and phylogenetic tree analysis, and that data were matched with those of the clinical isolates. Among the 70 Acinetobacter spp. sewage isolates tested, A. baumannii was the most prevalent and detectable in 5 hospitals, followed by A. nosocomialis and A. gerneri. Worryingly, 57.14 % (40/70) of the isolates were MDR, with 25.71 % (18/70) being resistant to carbapenem. When utilizing the Pasteur scheme, ST2 was the predominant type among these CRAB isolates, with Tn2006 (ΔISAba1-blaOXA-23-ATPase-yeeB-yeeA-ΔISAba1) and Tn2009 (ΔISAba1-blaOXA-23-ATPase-hp-parA-yeeC-hp-yeeB-ΔISAba1) being the key mobile genetic elements that encode carbapenem resistance. Seven A. gerneri isolates which harbored Tn2008 (ISAba1-blaOXA-23 -ATPase) and the blaPER-1 gene were also identified. Besides, an A. soil isolate was found to exhibit high-level of meropenem resistance (MIC ≥128 mg/L) and harbor a blaNDM-1 gene located in a core genetic structure of ISAba125-blaNDM-1-ble-trpF-dsbC-cutA. To investigate the genetic relatedness between isolates recovered from hospital sewage and those collected from ICUs, a phylogenetic tree was constructed for 242 clinical isolates and 9 sewage isolates. The results revealed the presence of two evolutionary clades, each containing isolates from both ICU and sewage water, suggesting that CRAB isolates in untreated sewage water were also the transmission clones or closely related evolutionary isolates recoverable in hospital settings. Findings in this work confirm that hospital sewage is a potential reservoir of CRAB.

Outbreak caused by pandrug-resistant blaOXA-69/blaOXA-23/blaGES harboring Acinetobacter baumannii ST2 in an intensive care unit.

Acinetobacter baumannii has emerged as a main nosocomial pathogen exhibiting high rates of resistance to clinically relevant antibiotics. Six pandrug-resistant A. baumannii (PDR-A. baumannii) were recovered from three patients in a Tunisian Intensive Care Unit (ICU) between 10th and 16th of May 2018 resulting in one fatal case and raising the possibility of an outbreak. On 18th of May environmental screening of ICU surfaces was carried out. On 22nd of May a fourth patient was infected with PDR-A. baumannii and died. A second investigation was carried out for environmental screening and PDR-A. baumannii was isolated from the respirator. Antimicrobial susceptibility testing was performed according to EUCAST (2019) guidelines. MIC of colistin was determined by broth microdilution method. PCR was used to detect 14 beta-lactamases/carbapenemases and mcr (mcr-1 to mcr-5) genes. The genetic relatedness of PDR-A. baumannii isolates was determined by PFGE and MLST. Seven PDR-A. baumannii isolates were recovered from four patients, one MDR strain from wash basin, a PDR strain from hand sanitizer bottle and another PDR strain from respirator. All PDR-A. baumannii (n = 9) harbored blaOXA-69 gene and none carried mcr. Moreover, seven carried blaGES and blaOXA-23 genes. PFGE identified four pulsotypes (A, B, C, and D) with the pulsotype A gathering seven PDR-A. baumannii isolates: six from three patients and one from hygiene sample. MLST revealed that all PDR-A. baumannii isolates of pulsotype A belonged to the pandemic clone ST2. Systematic screening of MDR and PDR-A. baumannii is highly recommended to limit dissemination of such strains in ICUs.

A type 1 immunity-restricted promoter of the IL-33 receptor gene directs antiviral T-cell responses.

The pleiotropic alarmin interleukin-33 (IL-33) drives type 1, type 2 and regulatory T-cell responses via its receptor ST2. Subset-specific differences in ST2 expression intensity and dynamics suggest that transcriptional regulation is key in orchestrating the context-dependent activity of IL-33-ST2 signaling in T-cell immunity. Here, we identify a previously unrecognized alternative promoter in mice and humans that is located far upstream of the curated ST2-coding gene and drives ST2 expression in type 1 immunity. Mice lacking this promoter exhibit a selective loss of ST2 expression in type 1- but not type 2-biased T cells, resulting in impaired expansion of cytotoxic T cells (CTLs) and T-helper 1 cells upon viral infection. T-cell-intrinsic IL-33 signaling via type 1 promoter-driven ST2 is critical to generate a clonally diverse population of antiviral short-lived effector CTLs. Thus, lineage-specific alternative promoter usage directs alarmin responsiveness in T-cell subsets and offers opportunities for immune cell-specific targeting of the IL-33-ST2 axis in infections and inflammatory diseases.

Regulatory T cell-derived IL-1Ra suppresses the innate response to respiratory viral infection.

Regulatory T (Treg) cell modulation of adaptive immunity and tissue homeostasis is well described; however, less is known about Treg cell-mediated regulation of the innate immune response. Here we show that deletion of ST2, the receptor for interleukin (IL)-33, on Treg cells increased granulocyte influx into the lung and increased cytokine production by innate lymphoid and γδ T cells without alteration of adaptive immunity to influenza. IL-33 induced high levels of the interleukin-1 receptor antagonist (IL-1Ra) in ST2+ Treg cells and deletion of IL-1Ra in Treg cells increased granulocyte influx into the lung. Treg cell-specific deletion of ST2 or IL-1Ra improved survival to influenza, which was dependent on IL-1. Adventitial fibroblasts in the lung expressed high levels of the IL-1 receptor and their chemokine production was suppressed by Treg cell-produced IL-1Ra. Thus, we define a new pathway where IL-33-induced IL-1Ra production by tissue Treg cells suppresses IL-1-mediated innate immune responses to respiratory viral infection.

DHT and Insulin Upregulate Secretion of the Soluble Decoy Receptor of IL-33 From Decidualized Endometrial Stromal Cells.

Interleukin 33 (IL-33) signaling regulates most of the key processes of pregnancy, including decidualization, trophoblast proliferation and invasion, vascular remodeling, and placental growth. Accordingly, dysregulation of IL-33, its membrane-bound receptor (ST2L, transducer of IL-33 signaling), and its soluble decoy receptor (sST2, inhibitor of IL-33 signaling) has been linked to a wide range of adverse pregnancy outcomes that are common in women with obesity and polycystic ovary syndrome, that is, conditions associated with hyperandrogenism, insulin resistance, and compensatory hyperinsulinemia. To reveal if androgens and insulin might modulate uteroplacental IL-33 signaling, we investigated the effect of dihydrotestosterone (DHT) and/or insulin on the expression of ST2L and sST2 (along with the activity of their promoter regions), IL-33 and sIL1RAP (heterodimerization partner of sST2), during in vitro decidualization of endometrial stromal cells from 9 healthy women. DHT and insulin markedly upregulated sST2 secretion, in addition to the upregulation of its messenger RNA (mRNA) expression, while the proximal ST2 promoter, from which the sST2 transcript originates, was upregulated by insulin, and in a synergistic manner by DHT and insulin combination treatment. On the other hand, sIL1RAP was slightly downregulated by insulin and IL-33 mRNA expression was not affected by any of the hormones, while ST2L mRNA expression and transcription from its promoter region (distal ST2 promoter) could not be detected or showed a negligibly low level. We hypothesize that high levels of androgens and insulin might lead to subfertility and pregnancy complications, at least partially, through the sST2-dependent downregulation of uteroplacental IL-33 signaling.

Comparative genotypic characterization related to antibiotic resistance phenotypes of clinical carbapenem-resistant Acinetobacter baumannii MTC1106 (ST2) and MTC0619 (ST25).

BACKGROUND: The prevalence of Acinetobacter baumannii in nosocomial infections and its remarkable ability to develop antimicrobial resistance have been a critical issue in hospital settings. Here, we examined the genomic features related to resistance phenotype displayed by carbapenem-resistant A. baumannii (CRAB) MTC1106 (ST2) and MTC0619 (ST25). RESULTS: Resistome analysis of both strains revealed that MTC1106 possessed higher numbers of antimicrobial resistance genes compared to MTC0619. Some of those genetic determinants were present in accordance with the susceptibility profile of the isolates. The predicted ISAba1 region upstream of blaOXA-23 gene was related to carbapenem resistance since this IS element was well-characterized to mediate overexpression of carbapenemase genes and eventually provided capability to confer resistance. Unlike MTC0619 strain, which only carried class B and D ß-lactamase genes, MTC1106 strain also possessed blaTEM-1D, a class A ß-lactamase. Regarding to aminoglycosides resistance, MTC0619 contained 5 related genes in which all of them belonged to three groups of aminoglycosides modifying enzyme (AME), namely, N-acetyltransferase (AAC), O-nucleotidyltransferase (ANT), and O-phosphotransferase (APH). On the other hand, MTC1106 lacked only the AAC of which found in MTC0619, yet it also carried an armA gene encoding for 16S rRNA methyltransferase. Two macrolides resistance genes, mph(E) and msr(E), were identified next to the armA gene of MTC1106 isolate in which they encoded for macrolide 2'-phosphotransferase and ABC-type efflux pump, respectively. Besides acquired resistance genes, some chromosomal genes and SNPs associated with resistance to fluoroquinolones (i.e. gyrA and parC) and colistin (i.e. pmrCAB, eptA, and emrAB) were observed. However, gene expression analysis suggested that the genetic determinants significantly contributing to low-level colistin resistance remained unclear. In addition, similar number of efflux pumps genes were identified in both lineages with only the absence of adeC, a part of adeABC RND-type multidrug efflux pump in MTC0619 strain. CONCLUSIONS: We found that MTC1106 strain harbored more antimicrobial resistance genes and showed higher resistance to antibiotics than MTC0619 strain. Regarding genomic characterization, this study was likely the first genome comparative analysis of CARB that specifically included isolates belonging to ST2 and ST25 which were widely spread in Thailand. Taken altogether, this study suggests the importance to monitor the resistance status of circulating A. baumannii clones and identify genes that may contribute to shifting the resistance trend among isolates.

Characterization of a novel ArsR regulates divergent ars operon in Ensifer adhaerens strain ST2.

Microbes evolved resistance determinates for coping with arsenic toxicity are commonly regulated by a variety of transcriptional repressors (ArsRs). Ensifer adhaerens strain ST2 was previously shown tolerance to environmental organoarsenical methylarsenite (MAs(III)), which has been proposed to be a primordial antibiotic. In E. adhaerens strain ST2 chromosomal ars operon, two MAs(III) resistance genes, arsZ, encoding MAs(III) oxidase, and arsK, encoding MAs(III) efflux transporter, are controlled by a novel ArsR transcriptional repressor, EaArsR. It has two conserved cysteine pairs, Cys91-92 and Cys108-109. Electrophoretic mobility shift assays (EMSAs) demonstrate that EaArsR binds to two inverted-repeat sequences within the ars promoter between arsR and arsZ to repress ars operon transcription and that DNA binding is relieved upon binding of As(III) and MAs(III). Mutation of either Cys91 or Cys92 to serine (or both) abolished these mutants binding to the ars promoter. In contrast, both C108S and C109S mutants kept responsiveness to As(III) and MAs(III). These results suggest that cysteine pair Cys91-Cys92 and either Cys108 or Cys109 contribute to form arsenic binding site. Homology modeling of EaArsR indicates the binding site consisted of Cys91-Cys92 pair from one monomer and Cys108-Cys109 pair from the other monomer, which displays the diverse evolution of arsenic binding site in the ArsR metalloregulators.

The Role of the IL-33/ST2 Axis in CpG-Induced Macrophage Activation Syndrome.

Background: Macrophage activation syndrome (MAS) is a fatal inflammatory condition, which is often associated with the elevation of multiple proinflammatory cytokines and multiple organ dysfunction. Previous studies have shown that ST2 contributes to T cell overactivation and plays a detrimental role in mouse models of primary hemophagocytic lymphohistiocytosis. The purpose of this study was to investigate the role of the IL-33/ST2 axis in a mouse model of MAS induced by repeated injections of cytosine-phosphate-guanine (CpG). Methods: Serum cytokines were determined using the cytometric bead array by flow cytometry. IL-33 and ST2 were detected by immunohistochemistry and real-time quantitative PCR in the liver and spleen of mice. CD3 and F4/80 in the liver were detected by immunohistochemistry. Inflammatory macrophages and effector memory T lymphocytes were detected by flow cytometry. Result: The CpG-induced MAS model was successfully induced after repeated CpG injections, presenting with hypercytokinemia and hepatosplenomegaly. The numbers of IL-33 positive cells in the liver and spleen decreased significantly, while the expression of ST2 in the liver tended to increase in the mice with MAS. IL-33 and St2 knockout mice showed similar levels of hepatosplenomegaly, peripheral blood count, and cytokine storm when compared with wild-type (WT) mice after induction of MAS. There were also no significant differences in liver pathology (including inflammatory cell infiltration of CD3 and F4/80) and levels of splenic inflammatory macrophages and effector memory T cells between the WT and knockout mice. Conclusion: These results suggested that IL-33 decreased in the liver and spleen tissues of MAS mice. Further results suggest that IL-33 and St2 knockout mice have no treatment potential in CpG-induced MAS. Thus, the IL-33/ST2 axis has little effect on the prognosis of CpG-induced MAS.

TRAF4 is crucial for ST2+ memory Th2 cell expansion in IL-33-driven airway inflammation.

Tumor necrosis factor receptor-associated factor 4 (TRAF4) is an important regulator of type 2 responses in the airway; however, the underlying cellular and molecular mechanisms remain elusive. Herein, we generated T cell-specific TRAF4-deficient (CD4-cre Traf4fl/fl) mice and investigated the role of TRAF4 in memory Th2 cells expressing IL-33 receptor (ST2, suppression of tumorigenicity 2) (ST2+ mTh2 cells) in IL-33-mediated type 2 airway inflammation. We found that in vitro-polarized TRAF4-deficient (CD4-cre Traf4fl/fl) ST2+ mTh2 cells exhibited decreased IL-33-induced proliferation as compared with TRAF4-sufficient (Traf4fl/fl) cells. Moreover, CD4-cre Traf4fl/fl mice showed less ST2+ mTh2 cell proliferation and eosinophilic infiltration in the lungs than Traf4fl/fl mice in the preclinical models of IL-33-mediated type 2 airway inflammation. Mechanistically, we discovered that TRAF4 was required for the activation of AKT/mTOR and ERK1/2 signaling pathways as well as the expression of transcription factor Myc and nutrient transporters (Slc2a1, Slc7a1, and Slc7a5), signature genes involved in T cell growth and proliferation, in ST2+ mTh2 cells stimulated by IL-33. Taken together, the current study reveals a role of TRAF4 in ST2+ mTh2 cells in IL-33-mediated type 2 pulmonary inflammation, opening up avenues for the development of new therapeutic strategies.

Detrimental impact of the IL-33/ST2 axis in an animal infection model with Cryptococcus neoformans.

Cryptococcus neoformans and Cryptococcus gattii are pathogenic fungi that infect the human respiratory system and cause life-threatening pulmonary cryptococcosis. The immunopathology of cryptococcosis is completely different from that of other fungal allergies. In murine cryptococcal infection models, cryptococcal cells are usually injected via nasal or intratracheal routes. After the infection, the alveolar epithelial cells are impaired and release IL-33, an IL-1 family cytokine that functions as an alarmin. This cytokine detrimentally amplifies allergic responses, and also induces a protective immune response against parasitic infection. In the pulmonary cryptococcosis model, type-II alveolar epithelial cells are the major source of IL-33, and the alveolar epithelial cells, ILC2, and Th2 cells express the IL-33 receptor (ST2). In IL-33- or ST2-deficient mice, allergy-like immune responses are attenuated after the C. neoformans infection. The numbers of ILC2 and Th2 cells and the levels of type 2 cytokines, including IL-4, IL-5, and IL-13, are decreased in the mouse lungs in both models. In association with these changes, total blood IgE, bronchus mucus production, and the number of eosinophils are decreased. Conversely, lung neutrophils and M1-type macrophages are increased. These are protective immune subsets suppressing cryptococcal growth. As a result, the lung fungal burden of IL-33- and ST2-deficient mice is decreased post-infection, and both deficient mice show significantly improved mortality. This pathogenesis varies depending on the cryptococcal and murine strains used in the animal experiments. Here, we overview and discuss the itmmunopathology of the IL-33/ST2 axis in a murine lethal cryptococcal infection model.

The association of serum IL-33/ST2 expression with hepatocellular carcinoma.

BACKGROUND: IL-33 is a multifunctional cytokine with dual functions. However, the clinicopathological and prognostic significance of IL-33 in cancer patients, especially in patients with hepatocellular carcinoma (HCC), remains controversial. Therefore, we conducted a study of 565 patients with HCC and 561 healthy controls and performed a meta-analysis to quantitatively evaluate the above problems. METHODS: We collected blood from 565 patients with HCC and 561 healthy controls. ELISA was used to detect the concentrations of IL-33 and ST2 in the serum, and RT‒PCR was used to detect the levels of IL-33 and ST2 mRNA. Meanwhile, we collected comprehensive literature on IL-33 and the clinical characteristics of cancer patients retrieved from the PubMed, Web of Science and CNKI databases as of December 2022. An odds ratio (OR) with a 95% confidence interval (CI) was used to estimate the impact through overall and stratified analyses. RESULTS: Compared with the healthy control group, the levels of ST2 mRNA and serum in the peripheral blood of HCC patients increased (p < 0.05), while the levels of IL-33 mRNA and serum showed no significant difference between the two groups (p > 0.05). In the meta-analysis section, at the tissue level, the overall analysis showed that the expression of IL-33 was positively correlated with tumor stage, histological grade, distant metastasis, and tumor size. Compared with patients with low IL-33 expression, the 3-year overall survival (OS) rate (OR = 3.467, p < 0.001) and 5-year OS rate (OR = 2.784, p < 0.001) of patients with high IL-33 expression were lower. At the serum expression level, the overall analysis showed that the expression of IL-33 increased the risk of cancer, and the serum level of IL-33 was positively correlated with tumor stage and vascular invasion. CONCLUSION: IL-33/ST2 is a useful predictive or prognostic biomarker in clinical evaluation and may be used as a potential therapeutic target, but much research is needed to verify this hypothesis.

IL-33/ST2 axis of human amnion fibroblasts participates in inflammatory reactions at parturition.

BACKGROUND: Inflammation of the fetal membranes is an indispensable event of labor onset at both term and preterm birth. Interleukin-33 (IL-33) is known to participate in inflammation via ST2 (suppression of tumorigenicity 2) receptor as an inflammatory cytokine. However, it remains unknown whether IL-33/ST2 axis exists in human fetal membranes to promote inflammatory reactions in parturition. METHODS: The presence of IL-33 and ST2 and their changes at parturition were examined with transcriptomic sequencing, quantitative real-time polymerase chain reaction, Western blotting or immunohistochemistry in human amnion obtained from term and preterm birth with or without labor. Cultured primary human amnion fibroblasts were utilized to investigate the regulation and the role of IL-33/ST2 axis in the inflammation reactions. A mouse model was used to further study the role of IL-33 in parturition. RESULTS: Although IL-33 and ST2 expression were detected in both epithelial and fibroblast cells of human amnion, they are more abundant in amnion fibroblasts. Their abundance increased significantly in the amnion at both term and preterm birth with labor. Lipopolysaccharide, serum amyloid A1 and IL-1ß, the inflammatory mediators pertinent to labor onset, could all induce IL-33 expression through NF-κB activation in human amnion fibroblasts. In turn, via ST2 receptor, IL-33 induced the production of IL-1ß, IL-6 and PGE2 in human amnion fibroblasts via the MAPKs-NF-κB pathway. Moreover, IL-33 administration induced preterm birth in mice. CONCLUSION: IL-33/ST2 axis is present in human amnion fibroblasts, which is activated in both term and preterm labor. Activation of this axis leads to increased production of inflammatory factors pertinent to parturition, and results in preterm birth. Targeting the IL-33/ST2 axis may have potential value in the treatment of preterm birth.

Role of the IL-33/ST2 Activation Pathway in the Development of the Hepatic Fibrosis Induced by Schistosoma mansoni Granulomas in Mice.

Schistosoma mansoni eggs retained in host tissues induce innate cytokine release, contributing to the induction of Type-2 immune responses and granuloma formation, important to restrain cytotoxic antigens, but leading to fibrosis. Interleukin(IL)-33 participates in experimental models of inflammation and chemically induced fibrosis, but its role in S. mansoni-induced fibrosis is still unknown. To explore the role of the IL-33/suppressor of the tumorigenicity 2 (ST2) pathway, serum and liver cytokine levels, liver histopathology, and collagen deposition were comparatively evaluated in S. mansoni-infected wild-type (WT) and IL-33-receptor knockout (ST2-/-) BALB/c mice. Our data show similar egg counts and hydroxyproline in the livers of infected WT and ST2-/- mice; however, the extracellular matrix in ST2-/- granulomas was loose and disorganised. Pro-fibrotic cytokines, such as IL-13 and IL-17, and the tissue-repairing IL-22 were significantly lower in ST2-/- mice, especially in chronic schistosomiasis. ST2-/- mice also showed decreased α-smooth muscle actin (α-SMA) expression in granuloma cells, in addition to reduced Col III and Col VI mRNA levels and reticular fibres. Therefore, IL-33/ST2 signalling is essential for tissue repairing and myofibroblast activation during S. mansoni infection. Its disruption results in inappropriate granuloma organisation, partly due to the reduced type III and VI collagen and reticular fibre formation.

Clinical, Bacteriological, and Genetic Characterization of Bone and Joint Infections Involving Linezolid-Resistant Staphylococcus epidermidis: a Retrospective Multicenter Study in French Reference Centers.

The choice of the best probabilistic postoperative antibiotics in bone and joint infections (BJIs) is still challenging. Since the implementation of protocolized postoperative linezolid in six French referral centers, linezolid-resistant multidrug-resistant Staphylococcus epidermidis (LR-MDRSE) strains were isolated in patients with BJI. We aimed here to describe clinical, microbiological, and molecular patterns associated with these strains. All patients with at least one intraoperative specimen positive for LR-MDRSE between 2015 and 2020 were included in this retrospective multicenter study. Clinical presentation, management, and outcome were described. LR-MDRSE strains were investigated by MIC determination for linezolid and other anti-MRSA antibiotics, characterization of genetic determinants of resistance, and phylogenetic analysis. Forty-six patients (colonization n = 10, infection n = 36) were included in five centers, 45 had prior exposure to linezolid, 33 had foreign devices. Clinical success was achieved for 26/36 patients. Incidence of LR-MDRSE increased over the study period. One hundred percent of the strains were resistant to oxazolidinones, gentamicin, clindamycin, ofloxacin, rifampicin, ceftaroline, and ceftobiprole, and susceptible to cyclins, daptomycin, and dalbavancin. Susceptibility to delafloxacin was bimodal. Molecular analysis was performed for 44 strains, and the main mutation conferring linezolid resistance was the 23S rRNA G2576T mutation. All strains belonged to the sequence type ST2 or its clonal complex, and phylogenetic analysis showed emergence of five populations corresponding geographically to the centers. We showed the emergence of new clonal populations of highly linezolid-resistant S. epidermidis in BJIs. Identifying patients at risk for LR-MDRSE acquisition and proposing alternatives to systematic postoperative linezolid use are essential. IMPORTANCE The manuscript describes the emergence of clonal linezolid-resistant strains of Staphylococcus epidermidis (LR-MDRSE) isolated from patients presenting with bone and joint infections. Incidence of LR-MDRSE increased over the study period. All strains were highly resistant to oxazolidinones, gentamicin, clindamycin, ofloxacin, rifampicin, ceftaroline, and ceftobiprole, but were susceptible to cyclins, daptomycin, and dalbavancin. Susceptibility to delafloxacin was bimodal. The main mutation conferring linezolid resistance was the 23S rRNA G2576T mutation. All strains belonged to the sequence type ST2 or its clonal complex, and phylogenetic analysis showed emergence of five populations corresponding geographically to the centers. LR-MDRSE bone and joint infections seem to be accompanied by an overall poor prognosis related to comorbidities and therapeutic issues. Identifying patients at risk for LR-MDRSE acquisition and proposing alternatives to systematic postoperative linezolid use become essential, with a preference for parenteral drugs such as lipopeptids or lipoglycopeptids.