Cell-to-Cell Communications of cGAS-STING Pathway in Tumor Immune Microenvironment / 浙江大学学报·医学版

Targeting cGAS-STING pathway is a promising strategy in tumor treatment. The pattern recognition receptor cGAS identifies dsDNA and catalyzes the formation of the second messenger 2'3'-cGAMP, activating the downstream interferons and pro-inflammatory cytokines through the adaptor protein STING. Notably, in tumor immune microenvironment, key components of cGAS-STING pathway are transferred among neighboring cells. The intercellular transmission under these contexts serves to sustain and amplify innate immune responses while facilitating the emergence of adaptive immunity. The membrane-based system, including extracellular vesicles transport, phagocytosis and membrane fusion transmit dsDNA, cGAMP and activated STING, enhancing the immune surveillance and inflammatory. The membrane proteins, including specific protein channel and intercellular gap junctions, transfer cGAMP and dsDNA, which are crucial to regulate immune responses. And the ligand-receptor interactions for interferons transmission amplifies the anti-tumor response. This review elaborates on the regulatory mechanisms of cell-to-cell communications of cGAS-STING pathway in tumor immune microenvironment. We further explore how these mechanisms modulate immunological processes and discuss potential interventions and immunotherapeutic strategies targeting these signaling cascades.

Effects of Jiawei Jingqin Decoction （加味荆芩汤） on Inflammatory and Immune Responses in Rosacea Model Mice / 中医杂志

ObjectiveTo investigate the potential mechanisms of Jiawei Jingqin Decoction （加味荆芩汤） in the treatment of rosacea. MethodsFifty 8-week-old female BALB/c mice were randomly divided into normal control group， model group， and Jiawei Jingqin Decoction low， medium， and high-dose groups， with 10 mice in each group. Except for the normal control group， mice in the other groups were injected with 40μl of antimicrobial peptide LL-37 at a concentration of 320 μmol/L on the back， repeated once every 12 hours for a total of 4 injections， to induce the rosacea mouse model. The mice in the normal control group were injected with 40 μl of PBS solution at the same time. After successful modeling， the mice in the Jiawei Jingqin Decoction low， medium， and high-dose groups were orally administered Jiawei Jingqin Decoction at doses of 4.35， 8.71， and 17.42 g/（kg·d） respectively， while the mice in the normal control group and the model group were orally administered 20 ml/（kg·d） of normal saline. All groups were treated once daily for 5 days. The changes in skin lesions were observed， and the erythema area was measured and scored. Skin tissue at the injection site was collected for histopathological examination using HE staining， and the number of mast cells was detected using toluidine blue staining. The levels of interleukin-6 （IL-6）， interleukin-1β （IL-1β）， and tumor necrosis factor-alpha （TNF-α） in the skin lesion tissues were measured using the ELISA method. The mRNA expression levels of key factors in the innate immune response pathway of rosacea disease mechanism， including Toll-like receptor 2 （TLR2）， downstream molecules serine protease kallikrein 5 （KLK5） and matrix metalloproteinase 9 （MMP-9）， as well as related inflammatory factors （IL-1β， IL-6， TNF-α）， and adaptive immune CD4+ T cell-related factors interferon-gamma （INF-γ） mRNA were detected using RT-qPCR. Immunohistochemical staining was performed to detect the protein expression of KLK5， MMP-9， and the number of CD4+ T-positive cells. Western blot analysis was used to determine the protein expression levels of CD4+ T cell-related factors including IFN-γ， CC chemokine receptor 5 （CCR5）， signal transducer and activator of transcription 1 （STAT1）， signal transducer and activator of transcription 3 （STAT3）. ResultsThe skin at the injection site on the back of mice in the normal control group appeared normal without any skin lesions or erythema， and histopathological examination showed no infiltration of inflammatory cells. The model group had significantly higher erythema scores and larger erythema areas compared to the normal control group （P＜0.05）， and histopathological examination revealed a significant infiltration of inflammatory cells， with some signs of deep connective tissue damage. Compared to the model group， the Jiawei Jingqin Decoction medium and high-dose groups showed a significant decrease in erythema scores and erythema areas （P＜0.05）， as well as a reduction in inflammatory exudates and inflammatory cell infiltration. However， the Jiawei Jingqin Decoction low-dose group did not show significant difference （P＞0.05）， but there was a slight reduction in inflammatory cell infiltration compared to the model group. When compared to the normal control group， the rosacea skin tissues of the model group showed an increase in the number of mast cells， levels of IL-1β， IL-6， TNF-α， mRNA expression of IL-1β， IL-6， TNF-α， TLR2， INF-γ， KLK5， MMP-9， protein expression of KLK5， MMP-9， and the number of CD4+ T-positive cells （P＜0.05）. Compared to the model group， the Jiawei Jingqin Decoction medium and high-dose groups showed a decrease in the number of mast cells， levels of IL-1β， mRNA expression of IL-1β， TNF-α， and the number of CD4+ T-positive cells. The Jiawei Jingqin Decoction high-dose group showed a decrease in IL-6， TNF-α levels， mRNA expression of IL-6， TLR2， INF-γ， MMP-9， protein expression of MMP-9， KLK5， and the number of CD4+ T-positive cells， as well as a decrease in IFN-γ and STAT1 protein expression （P＜0.05） compared to the Model group. ConclusionJiawei Jingqin Decoction has significant improvement effect on the skin symptoms of roseacne in a mouse model. Its mechanism might be related to regulating skin immune inflammatory reactions， thereby reducing the release of pathogenic factors and inflammatory factors.

Research progress on the influence of TGF-β/Smad signaling pathway on host T cell immune responses in parasite infection / 中华地方病学杂志

Parasitic infection are an important global public health issue, and parasites can modulate and evade host immune attacks through various ways. In recent years, studies have shown that in the process of parasite infection, transforming growth factor-β (TGF-β)/Smad signaling pathway participates in host T cell immune response, induce T cells to proliferate and differentiate towards regulatory cells (Treg) and helper T cells (Th), regulate Treg/Th17 cell balance, inhibit Th1 cell proliferation and differentiation, and play an important role in the occurrence and development of parasitic diseases and their interactions with the host. This article reviews the research progress of T cell immune responses mediated by TGF-β/Smad signaling pathway in the process of parasite infection.

Immunogenic molecules associated with gut bacterial cell walls: chemical structures, immune-modulating functions, and mechanisms

Interactions between gut microbiome and host immune system are fundamental to maintaining the intestinal mucosal barrier and homeostasis. At the host-gut microbiome interface, cell wall-derived molecules from gut commensal bacteria have been reported to play a pivotal role in training and remodeling host immune responses. In this article, we review gut bacterial cell wall-derived molecules with characterized chemical structures, including peptidoglycan and lipid-related molecules that impact host health and disease processes via regulating innate and adaptive immunity. Also, we aim to discuss the structures, immune responses, and underlying mechanisms of these immunogenic molecules. Based on current advances, we propose cell wall-derived components as important sources of medicinal agents for the treatment of infection and immune diseases.

Immune responses of mucosal-associated invariant T cells in infectious diseases / 中华微生物学和免疫学杂志

Mucosal-associated invariant T (MAIT) cells are highly conserved immune cells that could participate in innate and adaptive immune responses after being activated by major histocompatibility complex class 1-related molecule (MR1) pathway or cytokine pathway. At present, it has been confirmed that a large number of MAIT cells exist in human peripheral blood and specific tissues, and play an important role in infectious diseases. This review focused on the role of MAIT cells in immune responses to different pathogens. Additionally, the therapeutic methods and challenges of targeting MAIT cells in infectious diseases were also discussed.

Stimuli-responsive nano vehicle enhances cancer immunotherapy by coordinating mitochondria-targeted immunogenic cell death and PD-L1 blockade

Induction of immunogenic cell death promotes antitumor immunity against cancer. However, majority of clinically-approved drugs are unable to elicit sufficient ICD. Here, our study revealed that mitochondria-targeted delivery of doxorubicin (DOX) massively amplified ICD via substantial generation of reactive oxygen species (ROS) after mitochondrial damage. The underlying mechanism behind increased ICD was further demonstrated to be ascribed to two pathways: (1) ROS elevated endoplasmic reticulum (ER) stress, leading to surface exposure of calreticulin; (2) ROS promoted release of various mitochondria-associated damage molecules including mitochondrial transcription factor A. Nevertheless, adaptive upregulation of PD-L1 was found after such ICD-inducing treatment. To overcome such immunosuppressive feedback, we developed a tumor stimuli-responsive nano vehicle to simultaneously exert mitochondrial targeted ICD induction and PD-L1 blockade. The nano vehicle was self-assembled from ICD-inducing copolymer and PD-L1 blocking copolymer, and possessed long-circulating property which contributed to better tumor accumulation and mitochondrial targeting. As a result, the nano vehicle remarkably activated antitumor immune responses and exhibited robust antitumor efficacy in both immunogenic and non-immunogenic tumor mouse models.

Fecal Microbiota Transplantation for Treatment of Inflammatory Bowel Disease: From Immune Response to Mechanism / 胃肠病学

Inflammatory bowel disease (IBD) is a chronic, recurrent, nonspecific inflammatory disease of gastrointestinal tract, and includes ulcerative colitis (UC) and Crohn's disease (CD). Many studies have shown that gut microbiota and its mediated immune responses are the key factors driving the development of IBD. Fecal microbiota transplantation (FMT) is widely recognized as a new and potentially effective method for the treatment of IBD, but the mechanism is unclear. This article reviewed the current application of FMT in IBD, the immune response and the microbiota-immune interaction mechanism after FMT for the treatment of IBD, so as to discuss the potential mechanism of FMT in IBD.

Effect of physicochemical properties on

Current advances of immunotherapy have greatly changed the way of cancer treatment. At the same time, a great number of nanoparticle-based cancer immunotherapies (NBCIs) have also been explored to elicit potent immune responses against tumors. However, few NBCIs are nearly in the clinical trial which is mainly ascribed to a lack understanding of

Host Cell Responses to Dengue Virus / 中山大学学报(医学科学版)

@#Recent outbreak of dengue virus （DENV） in subtropics and tropics and the increasing incidence of DENV infection have seriously threatened the public health. Upon virus infection，the host cells rapidly elicit various responses through activating different signaling pathways，to fight against the invasion of DENV. On the other hand，dengue virus has evolved many strategies of escaping，antagonizing or even utilizing these host responses. This review summarizes the progress of molecular biology of DENV and the cellular responses against DENV infection，including innate immune response，adaptive immune response，cell death，autophagy，unfolded protein response，and stress granule formation.

São Paulo School of Advanced Sciences on Vaccines: an overview

Two years ago, we held an exciting event entitled the São Paulo School of Advanced Sciences on Vaccines (SPSASV). Sixty-eight Ph.D. students, postdoctoral fellows and independent researchers from 37 different countries met at the Mendes Plaza Hotel located in the city of Santos, SP - Brazil to discuss the challenges and the new frontiers of vaccinology. The SPSASV provided a critical and comprehensive view of vaccine research from basics to the current state-of-the-art techniques performed worldwide. For 10 days, we discussed all the aspects of vaccine development in 36 lectures, 53 oral presentations and 2 poster sessions. At the end of the course, participants were further encouraged to present a model of a grant proposal related to vaccine development against individual pathogens. Among the targeted pathogens were viruses (Chikungunya, HIV, RSV, and Influenza), bacteria (Mycobacterium tuberculosis and Streptococcus pyogenes), parasites (Plasmodium falciparum or Plasmodium vivax), and the worm Strongyloides stercoralis. This report highlights some of the knowledge shared at the SPSASV.(AU)

Construction and characterization of a recombinant vaccine encoding the nucleocapsid protein gene of avian infectious bronchitis virus / Construção e caracterização de uma vacina recombinante codificando o gene da proteina do nucleocapsideo do virus da bronquite infecciosa das galinhas

A vacinação é a forma mais utilizada para prevenir a bronquite infecciosa causada pelo vírus da bronquite infecciosa das galinhas (IBV). Contudo, as vacinas convencionais são incapazes de diferenciar aves infectadas de vacinadas. No presente trabalho foi construído, caracterizado, e avaliado como candidato vacinal, um adenovírus recombinante expressando o gene N do IBV. O gene N foi clonado em um adenovírus humano tipo 5 defectivo e transfectado para as células HEK-293A para gerar rAd5_N. Após o vetor ser obtido como esperado e a confirmação da expressão da proteína N em HEK-293ª, foi realizada inoculação pela via oculo-nasal na dose de 10 7 TCID 50 /0,1mL para imunização de galinhas livres de patógenos específicos (SPF). A resposta imunológica do Ad5_N e a proteção contra o desafio ao IBV foram avaliadas e comparadas com uma vacina viva comercial. Não foram detectados anticorpos anti-IBV em aves vacinadas com o Ad5_N. A vacina comercial induziu anticorpos detectáveis a partir do 7º dia pós-vacinal. Em aves vacinadas com o Ad5_N não houve aumento na expressão de IFNγ. Neste estudo, o rAd5_N obtido não conferiu proteção contra desafio com IBV-M41. Os resultados indicam a necessidade de avaliar adenovírus recombinantes expressando outros genes do IBV.(AU)

Advance in drug treatment of autoimmune diseases / 中国药理学通报

Autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, etc.) are diseases characterized by local or systemic abnormal inflammatory immune response. At present, the treatment drugs of autoimmune diseases mainly include nonsteroid anti-inflammatory drugs, steroid anti-inflammatory drugs and disease modifying anti-rheumatic drugs (chemical medicine, natural medicine and biological agents), etc. With the pathological mechanism of autoimmune diseases to be clarified deeply and the discovery of new drug targets, new biological agents targeting cytokines and cell surface molecules have been developed rapidly. In recent years, multiple small molecule drugs targeting Janus kinase/ signal transducers and activators of transcription signaling pathway have been developed and applied in clinic. Soft regulation of inflammatory immune response drugs are the drugs with anti-inflammatory and immunomodulatory effects, as well as less adverse reactions. To develop this type of drug will be a new strategy and one of the main directions for the treatment of autoimmune diseases. The research progress of medicines to treat autoimmune diseases has been reviewed in this paper.

Regulation of Cellular Antiviral Signaling by Modifications of Ubiquitin and Ubiquitin-like Molecules

The initiation of cellular antiviral signaling depends on host pattern-recognition receptors (PRRs)-mediated recognition of viral nucleic acids that are known as classical pathogen-associated molecular patterns (PAMPs). PRRs recruit adaptor proteins and kinases to activate transcription factors and epigenetic modifiers to regulate transcription of hundreds of genes, the products of which collaborate to elicit antiviral responses. In addition, PRRs-triggered signaling induces activation of various inflammasomes which leads to the release of IL-1β and inflammation. Recent studies have demonstrated that PRRs-triggered signaling is critically regulated by ubiquitin and ubiquitin-like molecules. In this review, we first summarize an updated understanding of cellular antiviral signaling and virus-induced activation of inflammasome and then focus on the regulation of key components by ubiquitin and ubiquitin-like molecules.

Recent progress in microneme-based vaccines development against Toxoplasma gondii

Toxoplasmosis is a cosmopolitan zoonotic disease, which infect several warm-blooded mammals. More than one-third of the human population are seropositive worldwide. Due to the high seroprevalence of Toxoplasma gondii infection worldwide, the resulting clinical, mental, and economical complications, as well as incapability of current drugs in the elimination of parasites within tissue cysts, the development of a vaccine against T. gondii would be critical. In the past decades, valuable advances have been achieved in order to identification of vaccine candidates against T. gondii infection. Microneme proteins (MICs) secreted by the micronemes play a critical role in the initial stages of host cell invasion by parasites. In this review, we have summarized the recent progress for MIC-based vaccines development, such as DNA vaccines, recombinant protein vaccines, vaccines based on live-attenuated vectors, and prime-boost strategy in different mouse models. In conclusion, the use of live-attenuated vectors as vehicles to deliver and express the target gene and prime-boost regimens showed excellent outcomes in the development of vaccines against toxoplasmosis, which need more attention in the future studies.

Bergapten attenuates D-galactose-induced immunosenescence in BALB/c mice / 中国药理学与毒理学杂志

OBJECTIVE Bergapten (BG), is a furanocoumarin derived from herbal and citrus extracts can act as antioxidant and selective anticancer agents.The current study aimed to investigate whether bergapten would attenuate immunosenescence and to exploreits immunomodulatory effects on immune responses in D-galactose-induced aging BALB/c mice.METHODS Firstly,mice were given D-galactose(180 mg·kg-1)subcutaneous injections for 30 d.To evaluate the establishment of the aging-related effect in mice, serum samples of BALB/c mice were collected from tail vein. Aging BALB/c mice were freely divided into three groups: negative control group received 1% Tween 80 solution only, named D-gal group. Positive groups were received BG administration at the dose of 20 and 100 mg·kg-1, named D-gal+BG(20)group and D-gal+BG(100)group,respectively.Effects of bergapten on T lympho-cyte proliferation and flow cytometry were assessed by using the splenic cell suspension. Enzyme linked immunospot kits were used to quantitatively determine interferon-γ(IFN-γ)and interleukin-4(IL-4) levels of the isolated serum. Immunophenotype was determined by using mixture of antibodies includ-ing anti-CD3,anti-CD4,and anti-CD8.RESULTS Bergapten(20 mg·kg-1)therapy can modulate immu-nity against viral epidemics and attenuate aging-induced immune deficiency(P<0.01),which was correlat-ed with the decline in the activation of the Th and Tc responses in D-galactose induced aging BALB/c mice.According to the in vivo results,bergapten exposure up-regulated the secretion of IFN-γ and IL-4 in T-helper 1(Th1)and T helper 2(Th2)cells(P<0.05,P<0.01).Additionally,BG(20 mg·kg-1)restored antigen-specific CD4+and CD8+T cells in aging models (P<0.05, P<0.01), which may help to curing chronic infections. CONCLUSION The beneficial effect of bergapten in D-galactose induced aging BALB/c mice may be due to the Th and Tc responses activation.

IL-37b alleviates septic shock through inhibition of immune responses related to dendritic cells / 中国比较医学杂志

Objective To express the recombinant IL-37b protein and to investigate its role in the regulation of immune responses. Methods The prokaryotic expression vector pET28/IL-37b was constructed. The recombinant IL-37b protein was induced to be expressed and was purified using Ni2+-NTA gel column. C57BL/6 J mice were treated with IL-37b and injected with lipopolysaccharide(LPS)to induce septic shock,and the expression levels of IL-1β,IL-6,IFN-γ in the serum of the mice were detected. Dendritic cells from bone marrow of the mice were isolated and cultured, and were treated with IL-37b. After LPS-induced activation, the expression levels of marker molecules such as CD40, CD80 and MHCII on the cell surface, and cytokines such as IL-1β, IL-10, IL-12 and TNF-α in the culture supernatants were detected by flow cytometry. The CD4 +T cells from mice were isolated and the inhibitory effects of IL-37b on the expression of IFN-γ,TNF-α and IL-10 in the culture supernatants of T cells after induction by LPS were detected. Results IL-37b reduced the expression levels of proinflammatory cytokines in the serum of septic shock mice. IL-37b also inhibited the expression of co-stimulatory molecules and proinflammatory cytokines of the mouse dendritic cells, and suppress the activation of CD4 +T cells in vitro. Conclusions Purified recombinant IL-37b protein has high bioactivity, and can alleviate septic shock in organisms through inhibiting the activation of dendritic cells and related T cell immune responses.

The role of mitochondrial DNA in the regulation of innate immune responses / 医学研究生学报

Mitochondria is the main production site of oxidative phosphorylation and ATP, and it is famous as energy factory of the cell.In addition, mitochondria also participates in the process of cellular proliferation, differentiation and apoptosis, and signal transduction.Recent studies have revealed that pathophysiological functions of mitochondria beyond traditional energetic metabolism in cells.Mitochondria-released DAMPs, particularly mtDNA, could activate innate immune responses by involving TLR9, NLRP3 and cGAS-STING signaling pathways.In addition to facilitating antibacterial immunity and regulating antiviral signaling, mounting evidences suggest that mtDNA contributes to inflammatory diseases following cellular damage and apoptosis.In addition to its well-appreciated roles in cellular metabolism and ATP production, mtDNA appears to function as a key member in the innate immune system.Therefore, we highlight the emerging roles of mtDNA in innate immunity.

Direction of new drug research: soft regulation of inflammatory immune responses / 中国药理学与毒理学杂志

Inflammation reaction and immune response are inseparable at the levels of system, tissue, cell and molecule. Inflammatory immune responses (IIR) is defined a moderate or abnormal system responses of inflammatory immune related cells in responding to the internal and external environ-ment changes of body. Inflammatory immune related cells (traditionally, eg, macrophages, dendritic cells, T cells and B cells, etc, and non- traditionally, eg, glial cells, endothelial cells, epithelial cells, fibroblasts, synovial cells and liver cells, etc), and cytokines/receptor signal transduction involved in IIR. In current clinic drugs, such as inhibitors of COXs, inhibitors of TNF-alpha, IL-6, IL-17, BAFF etc, tradi?tional immunosuppressive drugs (eg, methotrexate, leflunomide) and novel kinase inhibitor (eg, JAKs inhibitor), suppress enzyme activity, gene synthesis and transcription, cytokines and receptor signal, etc, respectively. These drugs restrain the excessive activation function of inflammatory immune related cells, but at the same time, also inhibit the physiological response of these cells to signaling molecules, which cause physiological function disorder of cells and tissues, increase the risks of serious adverse drug reaction including infection and cancer. Soft regulation of inflammatory immune responses (SRIIR), that is regulating the activity of key molecules or interaction between molecules in cells and resulting in making excessive activation function back to normal physiological levels, is a novel direction of discovery and development of new drugs for the treatment of IIR related diseases.

Development of vaccines to Mycobacterium avium subsp. paratuberculosis infection

Johne's disease or paratuberculosis is a chronic debilitating disease in ruminants caused by Mycobacterium avium subsp. paratuberculosis (MAP). The disease causes significant economic losses in livestock industries worldwide. There are no effective control measures to eradicate the disease because there are no appropriate diagnostic methods to detect subclinically infected animals. Therefore, it is very difficult to control the disease using only test and cull strategies. Vaccination against paratuberculosis has been considered as an alternative strategy to control the disease when combined with management interventions. Understanding host-pathogen interactions is extremely important to development of vaccines. It has long been known that Th1-mediated cellular immune responses are play a crucial role in protection against MAP infection. However, recent studies suggested that innate immune responses are more closely related to protective effects than adaptive immunity. Based on this understanding, several attempts have been made to develop vaccines against paratuberculosis. A variety of ideas for designing novel vaccines have emerged, and the tests of the efficacy of these vaccines are conducted constantly. However, no effective vaccines are commercially available. In this study, studies of the development of vaccines for MAP were reviewed and summarized.

Soft regulation of inflammatory immune responses / 中国药理学通报

Inflammation reaction and immune response are in-separable in the levels of system, tissue, cell and molecule. In-flammatory immune responses ( IIR) is proposed in this paper, which is defined a moderate or abnormal system responses of in-flammatory immune related cells in responding to the internal and external environment changes of body. It is described briefly that the research progresses of inflammatory immune cells ( e. g. , macrophages, dendritic cells, T cells and B cells, etc. ) and non-inflammatory immune cells ( e. g. , glial cells, endothe-lial cells, epithelial cells, fibroblasts, synovial cells and liver cells, etc. ) , and cytokines/receptor signal transduction in-volved in IIR. Moreover, the existing problems about regulating IIR drugs clinically are summarized. It is firstly put forward that soft regulation of inflammatory immune responses ( SRIIR) is a new direction of discovery and development of new drugs for the treatment of IIR related diseases.