Psychological stress to ovalbumin peptide-specific T-cell receptor transgenic mice impairs the suppressive ability of type 1 regulatory T cell.

Numerous diseases of the immune system can be traced back to the malfunctioning of the regulatory T cells. The aetiology is unclear. Psychological stress can cause disruption to the immune regulation. The synergistic effects of psychological stress and immune response on immune regulation have yet to be fully understood. The intention of this study is to analyse the interaction between psychological stress and immune responses and how it affects the functional status of type 1 regulatory T (Tr1) cells. In this study, ovalbumin peptide T-cell receptor transgenic mice were utilised. Mice were subjected to restraint stress to induce psychological stress. An airway allergy murine model was established, in which a mouse strain with RING finger protein 20 (Rnf20)-deficient CD4+ T cells were used. The results showed that concomitant exposure to restraint stress and immune response could exacerbate endoplasmic reticulum stress in Tr1 cells. Corticosterone was responsible for the elevated expression of X-box protein-1 (XBP1) in mouse Tr1 cells after exposure to both restraint stress and immune response. XBP1 mediated the effects of corticosterone on inducing Rnf20 in Tr1 cells. The reduction of the interleukin-10 expression in Tr1 cells was facilitated by Rnf20. Inhibition of Rnf20 alleviated experimental airway allergy by restoring the immune regulatory ability of Tr1 cells. In conclusion, the functions of Tr1 cells are negatively impacted by simultaneous exposure to psychological stress and immune response. Tr1 cells' immune suppressive functions can be restored by inhibiting Rnf20, which has the translational potential for the treatment of diseases of the immune system.

The signaling pathways involved in non-coding RNA regulation during osteogenic differentiation of periodontal tissue-derived cells in the field of periodontitis.

Periodontitis is a prevalent oral disease caused by chronic inflammation of the periodontal tissues surrounding the teeth, which can lead to bone loss, tooth loosening, and even tooth loss. This inflammation has a negative impact on the osteogenic differentiation capacity of periodontal tissue-derived cells. Non-coding RNAs (ncRNAs) are a class of RNA molecules that do not encode proteins but can regulate various physiological processes. In this review, we summarized the critical signaling pathways that ncRNAs modulate in osteogenic differentiation of periodontal tissue-derived cells, such as the Wnt, BMP/Smad, NF-κB, and PI3-K/Akt/mTOR pathways. This comprehensive exploration of ncRNA-mediated modulation offers fresh and promising insights for prospective approaches in the management of periodontitis and the advancement of periodontal regeneration therapies.

5-HT is associated with the dysfunction of regulating T cells in patients with allergic rhinitis.

The dysfunction of regulating T lymphocytes (Treg) is associated with the pathogenesis of many diseases. 5-hydroxytryptamine (5-HT) is capable of interacting with immune cells. The objective of the present study is to shed light on the role of 5-HT in regulating Treg activities. Blood samples were collected from patients with perennial allergic rhinitis (AR). Tregs were isolated from blood samples by magnetic cell sorting. The levels of 5-HT and other cytokines were determined by enzyme-linked immunosorbent assay. The results showed that serum 5-HT levels in patients with AR were higher than in healthy control (HC) subjects. A positive correlation was identified in the data between 5-HT concentrations and AR-related cytokine concentrations in the serum. A negative correlation was found between serum levels of 5-HT and the peripheral frequency of Treg. Exposure to 5-HT enhanced the expression of IL-6 and IL-21 in dendritic cells (DC). Co-culture of 5-HT-primed DCs with Tregs led to the conversion of Th17 cells. STAT3 blockade efficiently abolished the 5-HT-associated conversion of Th17 cells from Tregs. In summary, patients with AR exhibited higher serum concentrations of 5-HT. 5-HT-primed DCs could convert Tregs to Th17 cells.

Recent advances in glioma microenvironment-response nanoplatforms for phototherapy and sonotherapy.

The newly emerging nanotheranostic strategies including photodynamic therapy (PDT), photothermal therapy (PTT) and sonodynamic therapy (SDT) have exhibited their unbeatable advantages in treatment and prognosis of glioma tumors as compared to conventional ones like chemotherapy, radiotherapy and surgery. Meanwhile, the components of glioma microenvironment including blood brain barrier (BBB), oxidative stress, hypoxia and angiogenesis, play essential roles in glioma initiation, progression, invasion, recurrence and drug resistance. More importantly, the nanoparticles can modulate the glioma environments to increase targeting capability, monitor the glioma growth, and enhance therapy outcomes. In this review, we will introduce the basic components of glioma microenvironment, the role that glioma microenvironment played on tumor development and progression, and the key perspectives associated with glioma microenvironment-based multifunctional nanoplatform design. In particular, recent advances in glioma microenvironment-response nanoparticles for phototherapy (PTT and PDT) and sonotherapy will be discussed in detail. Finally, the challenges related to the clinical transition for nanomedicine-based glioma theranostics will be addressed.

CARsomes inhibit airway allergic inflammation in mice by inducing antigen-specific Th2 cell apoptosis.

BACKGROUND: Skewed T helper (Th)2 response plays a crucial role in the pathogenesis of allergic diseases. The therapeutic efficacy for allergic diseases is unsatisfactory currently. This study aims to regulate the skewed Th2 response with CARsomes. METHODS: The CARsome consisted of an epitope of Dermatophagoides farina-1 (Derf1), a segment of the anti-DEC205 antibody, the scFv, and an open reading frame of perforin. This fusion protein binds to DEC205 molecule on the surface of exosomes derived from dendritic cells (DC). The effects of CARsome on inducing antigen (Ag)-specific Th2 cell apoptosis were assessed both in vivo and in vitro. RESULTS: Exposure to CARsomes in the culture induced Ag-specific Th2 cell apoptosis. Injection of CARsomes through the vein puncture also induced Ag-specific Th2 cell apoptosis in the lungs of sensitized mice. CARsomes could induce Ag-specific regulatory T cells. Administration of CARsomes efficiently inhibited experimental allergic airway inflammation. CONCLUSIONS: The CARsomes can inhibit allergic airway inflammation by inducing Ag-specific Th2 cell apoptosis and induce Ag-specific regulatory T cells. The data suggest that CARsomes have the translational potential to be used to treat allergic airway inflammation.

Thrombospondin-1 (TSP1)-producing B cells restore antigen (Ag)-specific immune tolerance in an allergic environment.

Restoration of the antigen (Ag)-specific immune tolerance in an allergic environment is refractory. B cells are involved in immune regulation. Whether B cells facilitate the generation of Ag-specific immune tolerance in an allergic environment requires further investigation. This paper aims to elucidate the mechanism by which B cells restore the Ag-specific immune tolerance in an allergic environment. In this study, a B cell-deficient mouse model was created by injecting an anti-CD20 antibody. The frequency of tolerogenic dendritic cell (TolDC) was assessed by flow cytometry. The levels of cytokines were determined by enzyme-linked immunosorbent assay. The expression of thrombospondin-1 (TSP1) was assessed by quantitative real-time RT-PCR, Western blotting, and methylation-specific PCR. The results showed that B cells were required in the generation of the TGF-ß-producing TolDCs in mice. B cell-derived TSP1 converted the latent TGF-ß to the active TGF-ß in DCs, which generated TGF-ß-producing TolDCs. Exposure to IL-13 inhibited the expression of TSP1 in B cells by enhancing the TSP1 gene DNA methylation. Treating food allergy mice with Ag-specific immunotherapy and IL-13 antagonists restored the generation of TolDCs and enhanced the effect of specific immunotherapy. In conclusion, B cells play a critical role in the restoration of specific immune tolerance in an allergic environment. Blocking IL-13 in an allergic environment facilitated the generation of TolDCs and enhanced the therapeutic effect of immunotherapy.

Allergen-specific immune response suppresses interleukin 10 expression in B cells via increasing micro-RNA-17-92 cluster.

Interleukin (IL)-10-expressing B cells play a critical role in the immune homeostasis in the body; its regulation has not been fully understood. Micro-RNA (miR)-17-92 cluster has strong regulation in the immunity. This study tests a hypothesis that miR-17-92 cluster suppresses IL-10 expression in B cells. In this study, peripheral B cells were collected from patients with allergic rhinitis (AR). The B cells were treated with specific allergens, dust mite extracts, in the culture. The expressions of miR-17-92 cluster and IL-10 in the culture were assessed by real-time quantitative reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay. The results showed that the levels of miR-19a, but not the rest of the 5 members (miR-17, miR-18a, miR-19b, miR-20a, and miR-92a), were significantly higher in peripheral B cells from AR patients as than in B cells from healthy participants. Exposure of B cells from AR patients to specific allergen, dust mite extracts, significantly increased the levels if miR-19a and suppressed the expression of IL-10 in B cells. The levels of histone deacetylase 11 and acetylated H3K9 were higher, and the RNA polymerase II and c-Maf (the IL-10 transcription factor) were lower, at the IL-10 promoter locus. In conclusion, miR-19a mediates the allergen-specific immune response-decreased IL-10 expression in B cells.

Insulin-like growth factor-2 enhances functions of antigen (Ag)-specific regulatory B cells.

Regulatory B cells (Bregs) are important in immune regulation. The factors that regulate Breg functions are less clear. Insulin-like growth factor 2 (IGF2) is capable of inducing hematopoietic stem cell differentiation. This study aimed to investigate the role of IGF2 in the development of Bregs and the enhancement of their function. In this study, the expression of IGF1 receptor (IGF1R) and IGF2R in ovalbumin (OVA)-specific B cells (OVAsBCs) was assessed by real time RT-PCR and Western blotting. The release of interleukin (IL)-10 from OVAsBCs and OVAsBC proliferation were assessed by enzyme-linked immunoassay and proliferation assay. The role of IGF2 in enhancing the function of OVAsBCs was tested with an intestinal allergic inflammation mouse model. The results showed that OVAsBCs expressed high levels of IGF2R. Exposure to both IGF2 and a specific antigen (Ag), OVA, markedly enhanced the expression of IL-10 in OVAsBCs as well as enhanced the IL-10(+) OVAsBC proliferation. The concurrent exposure to IGF2 and specific Ag markedly induced the IL-10 promoter DNA demethylation via activating the STAT5 pathway. IGF2 also enhanced both the OVAsBC proliferation in vivo and the effect of Ag-specific immunotherapy on inhibiting allergic inflammation in the intestine. We conclude that OVAsBCs express high levels of IGF2R and that IGF2 increases the expression of IL-10 in OVAsBCs and enhances OVAsBC proliferation and the inhibitory effect on allergic inflammation.

Insulin-like growth factor 2 enhances regulatory T-cell functions and suppresses food allergy in an experimental model.

BACKGROUND: The functions of regulatory T (Treg) cells are important in immunity, and the regulatory mechanisms of Treg cell activities are not fully understood yet. OBJECTIVES: We sought to investigate the role of insulin-like growth factor (IGF) 2 in the upregulation of Treg cell function. METHODS: The expression of insulin-like growth factor 2 receptor (IGF2R) on T cells was assessed by using flow cytometry. Treg cell functions were evaluated by assessing the suppressor effect on proliferation of other effector T (Teff) cells. The effect of IGF2 on regulating Treg cell functions were evaluated with a cell-culture model and a food allergy mouse model. RESULTS: Expression of IGF2R was observed in more than 90% of murine and human Treg cells but in less than 10% of effector CD4(+) T cells. Activation of IGF2R and T-cell receptor induced marked Treg cell proliferation and release of TGF-ß from Treg cells, which enhanced Treg cell immune suppressor effects on other Teff cell activities and allergic inflammation in the intestine. CONCLUSIONS: Activation of IGF2R enhances Treg cell functions in suppressing other Teff cell activities and inhibiting allergic inflammation in the intestine.

Prolactin mediates psychological stress-induced dysfunction of regulatory T cells to facilitate intestinal inflammation.

OBJECTIVE: The dysfunction of immune regulation plays a critical role in the pathogenesis of a number of chronic inflammatory disorders, such as IBD. A close relationship between psychological stress and intestinal inflammation has been noted; the underlying mechanism remains elusive. This study aims to elucidate a pathological pathway between psychological stress and the dysfunction of regulatory T cells (Treg), and its effect on facilitating intestinal inflammation. DESIGN: A restraint stress model was employed to induce psychological stress in mice. The functions of Tregs were determined by assessing the immune suppressor effects in the intestine. A mouse model of intestinal inflammation was established using a low dose of trinitrobenzene sulfonic acid (TNBS) or dextran sulfate sodium (DSS) together with the challenge of chronic stress. RESULTS: After treating mice with restraint stress, the suppressor function of intestinal Treg was compromised, although the frequency of Treg was not changed in the intestine. Further observation revealed that stress induced Tregs in the intestine to differentiate into foxhead box P3(+) interleukin (IL)-17(+) tumour necrosis factor (TNF)-α(+) T cells. We also observed that exposure to stress-derived prolactin induced dendritic cells (DC) to produce IL-6 and IL-23 in vitro and in vivo, which played a critical role in altering Treg's phenotypes. Treating mice with chronic stress facilitated the initiation of intestinal inflammation by a low dose of TNBS or DSS, which was abolished by pretreatment with an inhibitor of prolactin, the cabergoline. CONCLUSIONS: Psychological stress-derived prolactin alters DC and Treg's properties to contribute to intestinal inflammation.

The Combination of Membrane Disruption and FtsZ Targeting by a Chemotherapeutic Hydrogel Synergistically Combats Pathogens Infections.

The emergence of multidrug-resistant (MDR) bacteria poses a significant challenge to global health. Due to a shortage of antibiotics, alternative therapeutic strategies are urgently needed. Unfortunately, colistin, the last-resort antibiotic, has unavoidable nephrotoxicity and hepatotoxicity, and its single killing mechanism is prone to drug resistance. To address this challenge, a promising combinatorial approach that includes colistin, a membrane-disrupting antimicrobial agent, and chelerythrine (CHE), a FtsZ protein inhibitor is proposed. This approach significantly reduces antibiotic dose and development of resistance, leading to almost complete inactivation of MDR pathogens in vitro. To address solubility issues and ensure transport, the antimicrobial hydrogel system LNP-CHE-CST@hydrogel, which induced reactive oxygen species (ROS) and apoptosis-like cell death by targeting the FtsZ protein, is used. In an in vivo mouse skin infection model, the combination therapy effectively eliminated MDR bacteria within 24 h, as monitored by fluorescence tracking. The findings demonstrate a promising approach for developing multifunctional hydrogels to combat MDR bacterial infections.

Natural Fat Nanoemulsions for Enhanced Optical Coherence Tomography Neuroimaging and Tumor Imaging in the Second Near-Infrared Window.

Optical coherence tomography (OCT) imaging mainly uses backscattered light to visualize the structural and functional information on biological tissues. In particular, OCT angiography can not only map the capillary networks but also capture the blood flow in the tissue microenvironment, making it a good candidate for neuroimaging and tumor imaging in vivo and in real time. To further improve the detection accuracy of cancer or brain disorders, it is essential to develop a natural and nontoxic contrast agent for enhanced OCT imaging in the second near-infrared (NIR-II) window. In this study, a superior biocompatible and highly scattering NIR-II fat nanoemulsion was constructed to improve OCT imaging contrast and depth for monitoring the vascular network changes of the cerebral cortex or tumor. In vivo experimental results demonstrated that a natural fat nanoemulsion can serve as an excellent probe for enhanced OCT neuroimaging and tumor imaging.

Supercharged precision killers: Genetically engineered biomimetic drugs of screened metalloantibiotics against Acinetobacter baumanni.

To eliminate multidrug-resistant bacteria of Acinetobacter baumannii, we screened 1100 Food and Drug Administration-approved small molecule drugs and accessed the broxyquinoline (Bq) efficacy in combination with various metal ions. Antibacterial tests demonstrated that the prepared Zn(Bq)2 complex showed ultralow minimum inhibitory concentration of ~0.21 micrograms per milliliter with no resistance after 30 passages. We then constructed the nano zeolitic imidazolate framework-8 (ZIF-8) as a drug carrier of Zn(Bq)2 and also incorporated the photosensitizer chlorin e6 (Ce6) to trace and boost the antibacterial effect. To further ensure the stable and targeted delivery, we genetically engineered outer membrane vesicles (OMVs) with the ability to selectively target A. baumannii. By coating the ZnBq/Ce6@ZIF-8 core with these OMV, the resulted drug (ZnBq/Ce6@ZIF-8@OMV) exhibited exceptional killing efficacy (>99.9999999%) of A. baumannii. In addition, in vitro and in vivo tests were also respectively carried out to inspect the remarkable efficacy of this previously unknown nanodrug in eradicating A. baumannii infections, including biofilms and meningitis.

Ubiquitin E3 ligase A20 facilitates processing microbial product in nasal epithelial cells.

Microbial products play a role in the pathogenesis of allergic diseases; ubiquitin E3 ligase A20 (A20) is an important molecule in regulating inflammation in the body. The present study aims to elucidate the role of A20 in processing the absorbed microbial products in nasal epithelial cells. Human nasal mucosal specimens were collected from patients with or without chronic rhinitis and analyzed by immunohistochemistry. Human nasal epithelial cell line, RPMI2650 cell, was employed to assess the role of A20 in processing the absorbed staphylococcal enterotoxin B (SEB). The RPMI2650 cells absorbed SEB in the culture. The increase in A20 was observed in RPMI2650 cells in parallel to the absorption of SEB. A20 is a critical molecule in the degradation of SEB in the nasal epithelial cells by promoting the tethering of endosomes and lysosomes. A20 plays a critical role in processing of the absorbed SEB in nasal epithelial cells.

Corticotropin releasing hormone activates CD14+ cells to induce endothelial barrier dysfunction.

Endothelial barrier dysfunction is associated with the pathogenesis of a number of disorders in the body, but the aetiology is unclear. We have investigated the mechanism of the psychological stress mediator, corticotropin releasing hormone (CRH), on compromising the endothelial barrier function. Human endothelial cell line, Hmvec cells, was cultured in monolayers as a model of endothelial barrier. Human peripheral CD14+ cells were collected to be used as effector immune cells. The transepithelial resistance (TER) and permeability of horseradish peroxidase (HRP) were used as indicators of endothelial barrier function. Apoptosis in Hmvec cells were analysed by flow cytometry. Human CD14+ cells expressed both receptors (R) of CRH, the CRH-R1 and CRH-R2. Exposure to CRH induced CD14+ cells to release tumour necrosis factor (TNF)-α. CRH-activated CD14+ cells decreased TER and increased the permeability to HRP in co-cultured Hmvec monolayers. Co-culture with CRH-activated CD14+ cells increased the apoptosis in Hmvec cells. We conclude that CRH can activate CD14+ cells to produce TNF-α and compromise endothelial barrier function by inducing apoptosis of the endothelial cells.

Ultrasound nanotheranostics: Toward precision medicine.

Ultrasound (US) is a mechanical wave that can penetrate biological tissues and trigger complex bioeffects. The mechanisms of US in different diagnosis and treatment are different, and the functional application of commercial US is also expanding. In particular, recent developments in nanotechnology have led to a wider use of US in precision medicine. In this review, we focus on US in combination with versatile micro and nanoparticles (NPs)/nanovesicles for tumor theranostics. We first introduce US-assisted drug delivery as a stimulus-responsive approach that spatiotemporally regulates the deposit of nanomedicines in target tissues. Multiple functionalized NPs and their US-regulated drug-release curves are analyzed in detail. Moreover, as a typical representative of US therapy, sonodynamic antitumor strategy is attracting researchers' attention. The collaborative efficiency and mechanisms of US and various nano-sensitizers such as nano-porphyrins and organic/inorganic nanosized sensitizers are outlined in this paper. A series of physicochemical processes during ultrasonic cavitation and NPs activation are also discussed. Finally, the new applications of US and diagnostic NPs in tumor-monitoring and image-guided combined therapy are summarized. Diagnostic NPs contain substances with imaging properties that enhance US contrast and photoacoustic imaging. The development of such high-resolution, low-background US-based imaging methods has contributed to modern precision medicine. It is expected that the integration of non-invasive US and nanotechnology will lead to significant breakthroughs in future clinical applications.

The transcription factor XBP1 in dendritic cells promotes the TH2 cell response in airway allergy.

Dendritic cells (DCs) that express T cell immunoglobulin domain molecule-4 (TIM4), a cell surface receptor for phosphatidylserine, induce T helper 2 (TH2) cell responses and allergic reactions. We elucidated the role of the transcription factor X-box-binding protein-1 (XBP1) in the induction of the TH2 cell response through its role in generating TIM4+ DCs. We found that XBP1 was required for TIM4 mRNA and protein expression in airway DCs in response to the cytokine interleukin-2 (IL-2) and that this pathway was required for TIM4 expression on DCs in response to the allergens PM2.5 and Derf1. The IL-2-XBP1-TIM4 axis in DCs contributed to Derf1/PM2.5-induced, aberrant TH2 cell responses in vivo. An interaction between the guanine nucleotide exchange factor Son of sevenless-1 (SOS1) and the GTPase RAS promoted XBP1 and TIM4 production in DCs. Targeting the XBP1-TIM4 pathway in DCs prevented or alleviated experimental airway allergy. Together, these data suggest that XBP1 is required for TH2 cell responses by inducing the development of TIM4+ DCs, which depends on the IL-2-XBP1-SOS1 axis. This signaling pathway provides potential therapeutic targets for the treatment of TH2 cell-dependent inflammation or allergic diseases.