Background/Objectives: The case we present is part of a large study that we conducted on hemodialysis patients with type 2 diabetes mellitus (T2DM) and which set the following objectives: studying changes in the intestinal microbiota, innate and acquired immune response capacity, and tissue regeneration. Methods: (1) For the genetic study of the gut microbiota, special techniques that are not based on cultivation were used since most of the species in the intestinal flora are not cultivable. (2) The immunological study had two targets: innate immunity (inflammation) and adaptive immunity (we chose to address the cellular immune response because, unlike the humoral one, it is insufficiently studied in this category of associated pathologies). As markers for innate immunity (inflammation), the following were determined: IL-6, sIL-6R, IL-1β, TNFα, IL-10, and NGAL. TNFβ/LTα was determined as a marker for adaptive immunity (the cellular immune response). (3) The study of tissue regeneration capacity was performed using NT-3 (this is the first study to do so) and VEGFβ (another marker that is scarce in this category of patients) as markers. All the aforementioned compounds were determined from serum samples, utilizing Merck Millipore ELISA kits for IL-6, IL-1β, IL-10, NT-3, and VEGF β, and Elabscience ELISA kits for IL-6R, TNFα, TNFβ, and NGAL. Results: We were very surprised to find unexpected immunological changes and tissue regenerative capacity in one of the patients studied, an 82-year-old female patient diagnosed with insulin-dependent T2DM with multiple complications, including end-stage renal disease (ESRD). The patient showed a huge capacity for tissue regeneration, combined with amplification of immunological capacity, in comparison to patients in the same group (T2DM and ESRD) and to those in the control group (ESRD). Thus, extremely elevated serum concentrations of IL-1β, IL-6, IL-10, and TNF-β, as well as the tissue regeneration indicators NT-3 and VEGFβ, were obtained in comparison to all other members of the patient group. At the same time, serum levels of the soluble IL-6 receptor (sIL6-R) and TNFα were greatly reduced compared to the test group's mean. Conclusions: All the data obtained during our research were corroborated with those from the specialized literature and entitle us to support the hypothesis that the cause of these unexpected behaviors is the genetically conditioned overproduction (possibly acquired post-infection) of IL-6, along with its predominant anti-inflammatory and pro-regenerative signaling through the membrane-bound receptor IL-6R.

Mycobacterium tuberculosis (Mtb) causes 1.25 million deaths a year. However, tuberculosis (TB) pathogenesis remains poorly understood and is not fully recapitulated in standard mouse models. Here we find that gene signatures from three different Mtb-susceptible mouse models predict active TB disease in humans significantly better than a signature from resistant C57BL/6 (B6) mice. Conserved among susceptible mice, non-human primates, and humans, but largely absent from B6 mice, was Mtb-induced differentiation of macrophages into an Spp1 + differentiation state. Spp1 + macrophages expressed high levels of immunosuppressive molecules including IL-1 receptor antagonist (IL-1Ra). IL-1Ra was previously reported to cause Mtb susceptibility in one mouse model, but whether IL-1Ra is broadly important remains uncertain. Here we report that enhancement of IL-1 signaling via deletion of IL-Ra promoted bacterial control across three susceptible mouse models. We found IL-1 signaling amplified production of multiple cytokines by lymphoid and stromal cells, providing a multifactorial mechanism for how IL-1 promotes Mtb control. Our results indicate that myeloid cell expression of immunosuppressive molecules, in particular IL-1 receptor antagonist, is a conserved early mechanism limiting Mtb control in mice, non-human primates, and humans.

Immunomodulatory agents have significant potential to enhance cancer treatment but have demonstrated limited efficacy beyond the preclinical setting owing to poor pharmacokinetics and toxicity associated with systemic administration. Conversely, when locally delivered, immunomodulatory agents require repeated administration to optimize immune stimulation. To overcome these challenges, we encapsulated the toll-like receptor 4 agonist monophosphoryl lipid A (MPLA) within hyperbranched polyglycerol-coated biodegradable nanoparticles (NPs) engineered for gradual drug release from the NP core, resulting in a more persistent stimulation of antitumor immune responses while minimizing systemic side effects. In a model of malignant melanoma, we demonstrate that hyperbranched polyglycerol-NP encapsulation significantly improves the antitumor efficacy of MPLA by enhancing its ability to remodel the tumor microenvironment. Relative to free MPLA, hyperbranched polyglycerol-coated NP-encapsulated MPLA significantly increased the NK cell- and cytotoxic T-cell-mediated antitumor immune response and tuned the tumor-draining lymph nodes toward a T helper 1 response. Furthermore, when combined with local delivery of a chemotherapeutic agent, hyperbranched polyglycerol-NP-MPLA induces the conversion of an immunosuppressive tumor microenvironment to immunogenic tumor microenvironment and significantly improves survival.

Microglia mediate the immune response in the central nervous system to many insults, including lipopolysaccharide (LPS), a bacterial endotoxin that initiates neuroinflammation in the neonatal population, especially preterm infants. The synthesis of the proinflammatory proteins CD40 and NLRP3 depends on the canonical NF-κB cascade as the genes encoding CD40 and NLRP3 are transcribed by the phosphorylated NF-κB p50/p65 heterodimer in LPS-induced microglia. Exosomes, which are nanosized vesicles (40-150 nm) involved in intercellular communication, are implicated in many pathophysiological processes. Human breast milk, which is rich in exosomes, plays a vital role in neonatal immune system maturation and adaptation. Activated microglia may cause brain-associated injuries or disorders; therefore, we hypothesize that human breast milk-derived exosomes (HBME) attenuate LPS-induced activation of CD40 and NLRP3 by decreasing p38 MAPK and NF-κB p50/p65 activation/phosphorylation downstream of TLR4 in murine microglia (BV2). Human microglia (HMC3) showed a significant decrease in p65 phosphorylation. We isolated purified HBME and characterized them using nanoparticle tracking analysis, transmission electron microscopy, fluorescence-activated cell sorting, and western blots. Analysis of microglia exposed to LPS and HBME indicated that HBME modulated the expression of signaling molecules in the canonical NF-κB pathway, including MyD88, IκBα, p38 MAPK, NF-κB p65, and their products CD40, NLRP3, and cytokines IL-1β and IL-10. Thus, HBMEs have great potential for attenuating the microglial response to LPS.

Background/Objectives: Inflammatory bowel diseases (IBDs) are chronic intestinal disorders with an unpredictable course. In parallel with the advent of new biologic therapies targeting specific interleukin pathways, end-point targets have become more stringent, aiming for mucosal and even histologic healing. Methods: We conducted a prospective study assessing immunohistochemical (IHC) parameters in 46 IBD patients treated with biologic therapy. A similar IHC analysis was performed for comparison with a cohort of 10 "non-IBD" patients. Results: The highest integrated optical density (IOD) of TNF-α was observed in patients with dysplasia, abscesses, mucin depletion and basal plasmacytosis. Non-responders had higher pre- and post-treatment TNF-α expression in both UC and CD compared to responders. On the contrary, the same analysis conducted in the subpopulation treated with anti-TNF-α therapy (Infliximab and Adalimumab) did not reveal a substantial difference in TNF-α expression between responders and non-responders. High pre-treatment interleukin-10 expression was associated with biologic therapy failure, histological inflammatory activity and longer disease duration. Conclusions: Pre-treatment assessment of IL-10 might be a useful tool for identifying a high-risk subset of IBD patients and determining a more aggressive therapy and intensive monitoring strategy.

Gliomas are the most frequent primary brain tumor and are essentially incurable. While nondiffuse gliomas are circumscribed, diffuse gliomas display an aggressive behavior characterized by tumor cell migration over large distances into the brain parenchyma, thereby precluding curative surgical resection. Almost all diffuse gliomas progress and recur as higher grades and become resistant to standard-of-care treatments. It is being increasingly recognized that glioma cells establish functional interactions with cells residing in the tumor microenvironment. Of these, tumor-associated microglia and macrophages (TAMs) play critical roles in immunosuppression through modulation of the extracellular matrix, and the secretion of molecules such as cytokines, neurotrophic factors, and micro-RNAs (miRNAs). Conversely, glioma cell signals influence cell states and drive the metabolic reprogramming of TAMs. Similarly, emergent evidence indicates that neuronal activity influences glioma by released factors and by establishing functional synapses with glioma cells to promote tumor growth and invasion. Glioma cells also affect local neuronal activities and maintain connections through microtube gap junctions to amplify local effects. Here, we discuss the molecular mechanisms underlying bidirectional interactions between glioma cells and TAMs, as well as between glioma cells and neurons. A better understanding of these cellular cross talks is crucial for the development of novel therapeutic strategies for diffuse gliomas.

Tumor-associated innate immune cells such as tumor-associated macrophages, neutrophils, dendritic cells play a crucial role in tumor progression, angiogenesis and metastasis. These cells also control the efficacy of chemotherapy and immunotherapy by inducing drug resistance and immunosuppression, leading to therapeutic failures. Therefore, targeting the tumor-associated innate immune cells has gained high attention for the development of effective cancer therapy. Nanomedicine based strategies to target these cells are highly relevant and can be used to reprogram these cells. In this review, we discuss the fundamental roles of the tumor-associated innate immune cells in the tumor microenvironment and different strategies to modulate them. Then, nanomedicine-based strategies to target different tumor innate immune cells are explained in detail. While the clinical development of the targeted nanomedicine remains a great challenge in practice, we have provided our perspectives on various factors such as pharmaceutical aspects, preclinical testing and biological aspects which are crucial to consider before translating these targeting strategies to clinics.

Immunosuppression in cancer poses challenges for immunotherapy and highlights the vulnerability of immunocompromised patients to viral infections. This study explored how Chikungunya virus (CHIKV) infection potentially inhibits B16-F10 melanoma-induced immunosuppressive effects on T cells and RAW 264.7 macrophages. We found high expression of CHIKV entry genes in melanoma and other cancers, with B16-F10 cells demonstrating greater susceptibility to CHIKV infection than non-tumorigenic cells. Interestingly, the CHIKV-infected B16-F10 cell culture supernatant (B16-F10-CS) reversed the immunosuppressive effects of uninfected B16-F10-CS on T cells. This reversal was characterised by decreased STAT3 activation and increased MAPK activation in T cells, an effect amplified by interleukin 10 (IL-10) receptor blockade. In RAW 264.7 cells, B16-F10-CS enhanced CHIKV infectivity without triggering activation. However, blocking the IL-10 receptor (IL-10R) in RAW 264.7 reduced CHIKV infection. CHIKV infection and IL-10R blockade synergistically inhibited B16-F10-CS-mediated polarisation of RAW 264.7 cells towards immunosuppressive macrophage. Our findings suggest that CHIKV modulates cancer-induced immunosuppression through IL-10-dependent pathways, providing new insights into viral-cancer interactions. This research may contribute to developing novel antiviral immunotherapies and virotherapies beneficial for cancer patients and immunocompromised individuals.

Immunosuppression is essential to ensure recipient and graft survivals after liver transplantation (LT). However, our understanding and management of the immune system remain suboptimal. Current immunosuppressive therapy cannot selectively inhibit the graft-specific immune response and entails a significant risk of serious side effects, i.e., among others, de novo cancers, infections, cardiovascular events, renal failure, metabolic syndrome, and late graft fibrosis, with progressive loss of graft function. Pharmacological research, aimed to develop alternative immunosuppressive agents in LT, is behind other solid-organ transplantation subspecialties, and, therefore, the development of new compounds and strategies should get priority in LT. The research trajectories cover mechanisms to induce T-cell exhaustion, to inhibit co-stimulation, to mitigate non-antigen-specific inflammatory response, and, lastly, to minimize the development and action of donor-specific antibodies. Moreover, while cellular modulation techniques are complex, active research is underway to foster the action of T-regulatory cells, to induce tolerogenic dendritic cells, and to promote the function of B-regulatory cells. We herein discuss current lines of research in clinical immunosuppression, particularly focusing on possible applications in the LT setting.

Food antigens elicit immune tolerance through the action of regulatory T cells (Tregs) in the intestine. Although antigens that trigger common food allergies are known, the epitopes that mediate tolerance to most foods have not been described. Here, we identified murine T cell receptors specific for maize, wheat, and soy, and used expression cloning to de-orphan their cognate epitopes. All of the epitopes derive from seed storage proteins that are resistant to degradation and abundant in the edible portion of the plant. Multiple unrelated T cell clones were specific for an epitope at the C-terminus of 19 kDa alpha-zein, a protein from maize kernel. An MHC tetramer loaded with this antigen revealed that zein-specific T cells are predominantly Tregs localized to the intestine. These cells, which develop concurrently with weaning, constitute up to 2% of the peripheral Treg pool. Bulk and single-cell RNA sequencing revealed that these cells express higher levels of immunosuppressive markers and chemokines compared to other Tregs. These data suggest that immune tolerance to plant-derived foods is focused on a specific class of antigens with common features, and they reveal the functional properties of naturally occurring food-specific Tregs.

Radiation therapy (RT) has been a primary treatment modality in cancer for decades. Increasing evidence suggests that RT can induce an immunosuppressive shift via upregulation of cells such as tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). MDSCs inhibit antitumor immunity through potent immunosuppressive mechanisms and have the potential to be crucial tools for cancer prognosis and treatment. MDSCs interact with many different pathways, desensitizing tumor tissue and interacting with tumor cells to promote therapeutic resistance. Vascular damage induced by RT triggers an inflammatory signaling cascade and potentiates hypoxia in the tumor microenvironment (TME). RT can also drastically modify cytokine and chemokine signaling in the TME to promote the accumulation of MDSCs. RT activation of the cGAS-STING cytosolic DNA sensing pathway recruits MDSCs through a CCR2-mediated mechanism, inhibiting the production of type 1 interferons and hampering antitumor activity and immune surveillance in the TME. The upregulation of hypoxia-inducible factor-1 and vascular endothelial growth factor mobilizes MDSCs to the TME. After recruitment, MDSCs promote immunosuppression by releasing reactive oxygen species and upregulating nitric oxide production through inducible nitric oxide synthase expression to inhibit cytotoxic activity. Overexpression of arginase-1 on subsets of MDSCs degrades L-arginine and downregulates CD3ζ, inhibiting T-cell receptor reactivity. This review explains how radiation promotes tumor resistance through activation of immunosuppressive MDSCs in the TME and discusses current research targeting MDSCs, which could serve as a promising clinical treatment strategy in the future.

Tumor immunity is a promising topic in the area of cancer therapy. The 'soil' function of the tumor microenvironment (TME) for tumor growth has attracted wide attention from scientists. Tumor-infiltrating immune cells in the TME, especially the tumor-infiltrating lymphocytes (TILs), serve a key role in cancer. Firstly, relevant literature was searched in the PubMed and Web of Science databases with the following key words: 'Tumor microenvironment'; 'TME'; 'tumor-infiltrating immunity cells'; 'gynecologic malignancies'; 'the adoptive cell therapy (ACT) of TILs'; and 'TIL-ACT' (https://pubmed.ncbi.nlm.nih.gov/). According to the title and abstract of the articles, relevant items were screened out in the preliminary screening. The most relevant selected items were of two types: All kinds of tumor-infiltrating immune cells; and advanced research on TILs in gynecological malignancies. The results showed that the subsets of TILs were various and complex, while each subpopulation influenced each other and their effects on tumor prognosis were diverse. Moreover, the related research and clinical trials on TILs were mostly concentrated in melanoma and breast cancer, but relatively few focused on gynecological tumors. In conclusion, the present review summarized the biological classification of TILs and the mechanisms of their involvement in the regulation of the immune microenvironment, and subsequently analyzed the development of tumor immunotherapy for TILs. Collectively, the present review provides ideas for the current treatment dilemma of gynecological tumor immune checkpoints, such as adverse reactions, safety, personal specificity and efficacy.

Cytotoxic T lymphocytes (CTLs) play critical antitumor roles, encompassing diverse subsets including CD4+, NK, and γδ T cells beyond conventional CD8+ CTLs. However, definitive CTLs biomarkers remain elusive, as cytotoxicity-molecule expression does not necessarily confer cytotoxic capacity. CTLs differentiation involves transcriptional regulation by factors such as T-bet and Blimp-1, although epigenetic regulation of CTLs is less clear. CTLs promote tumor killing through cytotoxic granules and death receptor pathways, but may also stimulate tumorigenesis in some contexts. Given that CTLs cytotoxicity varies across tumors, enhancing this function is critical. This review summarizes current knowledge on CTLs subsets, biomarkers, differentiation mechanisms, cancer-related functions, and strategies for improving cytotoxicity. Key outstanding questions include refining the CTLs definition, characterizing subtype diversity, elucidating differentiation and senescence pathways, delineating CTL-microbe relationships, and enabling multi-omics profiling. A more comprehensive understanding of CTLs biology will facilitate optimization of their immunotherapy applications. Overall, this review synthesizes the heterogeneity, regulation, functional roles, and enhancement strategies of CTLs in antitumor immunity, highlighting gaps in our knowledge of subtype diversity, definitive biomarkers, epigenetic control, microbial interactions, and multi-omics characterization. Addressing these questions will refine our understanding of CTLs immunology to better leverage cytotoxic functions against cancer.

Cestodes use own lipid-binding proteins to capture and transport hydrophobic ligands, including lipids that they cannot synthesise as fatty acids and cholesterol. In E. granulosus s.l., one of these lipoproteins is antigen B (EgAgB), codified by a multigenic and polymorphic family that gives rise to five gene products (EgAgB8/1-5 subunits) assembled as a 230 kDa macromolecule. EgAgB has a diagnostic value for cystic echinococcosis, but its putative role in the immunobiology of this infection is still poorly understood. Accumulating research suggests that EgAgB has immunomodulatory properties, but previous studies employed denatured antigen preparations that might exert different effects than the native form, thereby limiting data interpretation. This work analysed the modulatory actions on macrophages of native EgAgB (nEgAgB) and the recombinant form of EgAg8/1, which is the most abundant subunit in the larva and was expressed in insect S2 cells (rEgAgB8/1). Both EgAgB preparations were purified to homogeneity by immunoaffinity chromatography using a novel nanobody anti-EgAgB8/1. nEgAgB and rEgAgB8/1 exhibited differences in size and lipid composition. The rEgAgB8/1 generates mildly larger lipoproteins with a less diverse lipid composition than nEgAgB. Assays using human and murine macrophages showed that both nEgAgB and rEgAgB8/1 interfered with in vitro LPS-driven macrophage activation, decreasing cytokine (IL-1β, IL-6, IL-12p40, IFN-β) secretion and ·NO generation. Furthermore, nEgAgB and rEgAgB8/1 modulated in vivo LPS-induced cytokine production (IL-6, IL-10) and activation of large (measured as MHC-II level) and small (measured as CD86 and CD40 levels) macrophages in the peritoneum, although rEgAgB8/1 effects were less robust. Overall, this work reinforced the notion that EgAgB is an immunomodulatory component of E. granulosus s.l. Although nEgAgB lipid's effects cannot be ruled out, our data suggest that the EgAgB8/1 subunit contributes to EgAgB´s ability to regulate the inflammatory activation of macrophages.

The expression of costimulatory molecules such as MHC-II, CD86 and CD83 on dendritic cells (DCs) are strongly regulated during cellular activation. Ubiquitination of some of these markers by the E3 ubiquitin ligase MARCH-I affects the maturation state of DCs and subsequently modulates immune responses. The effects of MARCH-I gene overexpression on the functional activity of human DCs is not well understood. Here, we investigate how MARCH-I, regulates maturation of DCs. We now provide evidence that MARCH-I transduced DCs secrete high levels of IL10 despite low secretion of IL 6 and IL 12 in response to LPS stimulation. They are weak stimulators of T lymphocyte cells but skewed T cell polarization toward T regulatory subset. These results exhibit that reduced expression of surface costimulatory molecules suppresses DC activation. It can be concluded that overexpression of MARCH-I gene in DCs leads to the production of tolerogenic DC.

Brain tumors are a diverse collection of neoplasms affecting the brain with a high prevalence rate in people of all ages around the globe. In this pathological context, glioblastoma, a form of glioma that belongs to the IV-grade astrocytoma group, is the most common and most aggressive form of the primary brain tumors. Indeed, despite the best treatments available including surgery, radiotherapy or a pharmacological approach with Temozolomide, glioblastoma patients' mortality is still high, within a few months of diagnosis. Therefore, to increase the chances of these patients surviving, it is critical to keep finding novel treatment opportunities. In the past, efforts to treat glioblastoma have mostly concentrated on customized treatment plans that target specific mutations such as epidermal growth factor receptor (EGFR) mutations, Neurotrophic Tyrosine Receptor Kinase (NTRK) fusions, or multiple receptors using multi-kinase inhibitors like Sunitinib and Regorafenib, with varying degrees of success. Here, we focused on the receptor tyrosine kinase AXL that has been identified as a mediator for tumor progression and therapy resistance in various cancer types, including squamous cell tumors, small cell lung cancer, and breast cancer. Activated AXL leads to a significant increase in tumor proliferation, tumor cell migration, and angiogenesis in different in vitro and in vivo models of cancer since this receptor regulates interplay with apoptotic, angiogenic and inflammatory pathways. Based on these premises, in this review we mainly focused on the role of AXL in the course of glioblastoma, considering its primary biological mechanisms and as a possible target for the application of the most recent treatments.

Interleukin-10 (IL-10) is a key anti-inflammatory mediator in protecting host from over-exuberant responses to pathogens and play important roles in wound healing, autoimmunity, cancer, and homeostasis. However, its application as a therapeutic agent for biomedical applications has been limited due to its short biological half-life. Therefore, it is important to prolong the half-life of IL-10 to replace the current therapeutic application, which relies on administering large and repeated dosages. Therefore, not a cost-effective approach. Thus, studies that aim to address this type of challenges are always in need.

Recombinant IL-10 was encapsulated in biodegradable nanoparticles (Poly-(Lactic-co-Glycolic Acid) and Chitosan)) by the double emulsion method and then characterized for size, surface charge, thermal stability, cytotoxicity, in vitro release, UV-visible spectroscopy, and Fourier Transform-Infrared Spectroscopy as well as evaluated for its anti-inflammatory effects. Bioactivity of encapsulated IL-10 was evaluated in vitro using J774A.1 macrophage cell-line and in vivo using BALB/c mice. Inflammatory cytokines (IL-6 and TNF-α) were quantified from culture supernatants using specific enzyme-linked immunosorbent assay (ELISA), and significance was analyzed using ANOVA.

We obtained a high 96% encapsulation efficiency with smooth encapsulated IL-10 nanoparticles of ~100-150 nm size and release from nanoparticles as measurable to 22 days. Our result demonstrated that encapsulated IL-10 was biocompatible and functional by reducing the inflammatory responses induced by LPS in macrophages. Of significance, we also proved the functionality of encapsulated IL-10 by its capacity to reduce inflammation in BALB/c mice as provoked by Chlamydia trachomatis, an inflammatory sexually transmitted infectious bacterium.

Collectively, our results show the successful IL-10 encapsulation, slow release to prolong its biological half-life and reduce inflammatory cytokines IL-6 and TNF production in vitro and in mice. Our results serve as proof of concept to further explore the therapeutic prospective of encapsulated IL-10 for biomedical applications, including inflammatory diseases.

Lactoferrin (LF) is a glycoprotein that binds to iron ions (Fe2+) and other metallic ions, such as Mg2+, Zn2+, and Cu2+, and has antibacterial and immunomodulatory properties. The antibacterial properties of LF are due to its ability to sequester iron. The immunomodulatory capability of LF promotes homeostasis in the enteric environment, acting directly on the beneficial microbiota. LF can modulate antigen-presenting cell (APC) biology, including migration and cell activation. Nonetheless, some gut microbiota strains produce toxic metabolites, and APCs are responsible for initiating the process that inhibits the inflammatory response against them. Thus, eliminating harmful strains lowers the risk of inducing chronic inflammation, and consequently, metabolic disease, which can progress to type 2 diabetes mellitus (T2DM). LF and retinoic acid (RA) exhibit immunomodulatory properties such as decreasing cytokine production, thus modifying the inflammatory response. Their activities have been observed both in vitro and in vivo. The combined, simultaneous effect of these molecules has not been studied; however, the synergistic effect of LF and RA may be employed for enhancing the secretion of humoral factors, such as IgA. We speculate that the combination of LF and RA could be a potential prophylactic alternative for the treatment of metabolic dysregulations such as T2DM. The present review focuses on the importance of a healthy diet for a balanced gut and describes how probiotics and prebiotics with immunomodulatory activity as well as inductors of differentiation and cell proliferation could be acquired directly from the diet or indirectly through the oral administration of formulations aimed to maintain gut health or restore a eubiotic state in an intestinal environment that has been dysregulated by external factors such as stress and a high-fat diet.

The excessive production of IL-10, an anti-inflammatory cytokine, by Leishmania antigen-activated T cells is supposed to be a key player in the onset and progression of visceral leishmaniasis (VL). The IL-10-producing sources in VL remain unidentified and uncharacterized. In this study, we reveal that antigen-activated CD4+ T cells, i.e., CD44+CD4+ T cells expressing CD200R receptors, are the prime IL-10-producing phenotypes in Leishmania donovani infection-induced pathogenesis. These phenotypes are separate from CD25+Foxp3+CD4+ T regulatory cells, which are classical IL-10-producing phenotypes. In order to ascertain the role of CD200R and CD25 receptors in IL-10 overexpression-associated VL pathogenesis, we abrogated CD200R and CD25 receptor-mediated signaling in the infected mice. The splenic load of parasites and the size of the liver and spleen were significantly reduced in CD200-blocked mice as compared to CD25-blocked mice. Further, the CD200 blocking polarized CD4+ T cells to pro-inflammatory cytokines-producing phenotypes, as we observed a higher frequency of IFN-γ, TNF-α, and IL-12 positive cells as compared to controls including the CD25 blocking. Our findings suggest that in L. donovani infection-induced pathogenesis the expression of CD200R on antigen-activated T cells helps them to acquire IL-10-producing abilities as part of its one of the survival strategies. However, more studies would be warranted to better understand CD200R receptors role in VL pathogenesis and to develop the next generation of therapeutic and prophylactic control measures.

Gliomas are one of the most common primary malignant tumours of the central nervous system (CNS), of which glioblastomas (GBMs) are the most common and destructive type. The glioma tumour microenvironment (TME) has unique characteristics, such as hypoxia, the blood-brain barrier (BBB), reactive oxygen species (ROS) and tumour neovascularization. Therefore, the traditional treatment effect is limited. As cellular oxidative metabolites, ROS not only promote the occurrence and development of gliomas but also affect immune cells in the immune microenvironment. In contrast, either too high or too low ROS levels are detrimental to the survival of glioma cells, which indicates the threshold of ROS. Therefore, an in-depth understanding of the mechanisms of ROS production and scavenging, the threshold of ROS, and the role of ROS in the glioma TME can provide new methods and strategies for glioma treatment. Current methods to increase ROS include photodynamic therapy (PDT), sonodynamic therapy (SDT), and chemodynamic therapy (CDT), etc., and methods to eliminate ROS include the ingestion of antioxidants. Increasing/scavenging ROS is potentially applicable treatment, and further studies will help to provide more effective strategies for glioma treatment.

While the immune system plays a crucial role in the development of hypertension, the specific contributions of distinct immune cell populations remain incompletely understood. The emergence of single-cell RNA-sequencing (scRNA-seq) technology enables us to analyze the transcriptomes of individual immune cells and to assess the significance of each immune cell type in hypertension development.

We aimed to investigate the hypothesis that B cells play a crucial role in the development of fructose-induced hypertension.

Eight-week-old Dahl salt-sensitive (SS) male rats were divided into two groups and given either tap water (TW) or a 20% fructose solution (HFS) for 4 weeks. Systolic blood pressure was measured using the tail-cuff method. ScRNA-seq analysis was performed on lamina propria cells (LPs) and peripheral blood mononuclear cells (PBMCs) obtained from SS rats subjected to either TW or HFS. The HFS treatment induced hypertension in the SS rats. The analysis revealed 27 clusters in LPs and 28 clusters in PBMCs, allowing for the identification and characterization of various immune cell types within each cluster. Specifically, B cells and follicular helper T (Tfh) cells were prominent in LPs, while B cells and M1 macrophages dominated PBMCs in the HFS group. Moreover, the HFS treatment triggered an increase in the number of B cells in both LPs and PBMCs, accompanied by activation of the interferon pathway.

The significant involvement of B cells in intestinal and PBMC responses indicates their pivotal contribution to the development of hypertension. This finding suggests that targeting B cells could be a potential strategy to mitigate high blood pressure in fructose-induced hypertension. Moreover, the simultaneous increase in follicular B cells and Tfh cells in LPs, along with the upregulation of interferon pathway genes in B cells, underscores a potential autoimmune factor contributing to the pathogenesis of fructose-induced hypertension in the intestine.

Worldwide mortality from hepatic fibrosis remains high, due to hepatocellular carcinoma and end stage liver failure. The progressive nature of hepatic fibrosis from inflammation to cicatrized tissues warrants subtle intervention with pharmacological agents that hold potential. Empagliflozin (Empa), a novel hypoglycemic drug with antioxidant and anti-inflammatory properties, has lately been proposed to have additional antifibrotic activities. In the current study, we examined the antifibrotic effect of the Empa through modulating the activity of hepatic stellate cells by hedgehog (Hh) pathway. We also assessed the markers of inflammatory response and endoplasmic reticulum (ER) stress. Male Albino rats were treated with either CCl4 (0.4 mg/kg twice/week) and/or Empa (10 mg/kg/day) for eight weeks. In this study, CCl4 rats had active Hh signaling as indicated by overexpression of Patched 1, Smoothened and Glioblastoma-2. CCl4 induced ER stress as CHOP expression was upregulated and ERAD was downregulated. CCl4-induced inflammatory response was demonstrated through increased levels of TNF-α, IL-6 and mRNA levels of IL-17 while undetectable expression of IL-10. Conversely, Empa elicited immunosuppression, suppressed the expression of Hh markers, and reversed markers of ER stress. In conclusion, Empa suppressed CCl4-induced Hh signaling and proinflammatory response, meanwhile embraced ER stress in the hepatic tissues, altogether provided hepatoprotection.

Direct recognition of Mycobacterium tuberculosis (Mtb)-infected cells is required for protection by CD4+ T cells. While impaired T cell recognition of Mtb-infected macrophages was demonstrated in mice, data are lacking for humans. Using T cells and monocyte-derived macrophages (MDMs) from individuals with latent Mtb infection (LTBI), we quantified the frequency of memory CD4+ T cell activation in response to autologous MDMs infected with virulent Mtb. We observed robust T cell activation in response to Mtb infection of M1-like macrophages differentiated using GM-CSF, while M2-like macrophages differentiated using M-CSF were poorly recognized. However, non-infected GM-CSF and M-CSF MDMs loaded with exogenous antigens elicited similar CD4+ T cell activation. IL-10 was preferentially secreted by infected M-CSF MDMs, and neutralization improved T cell activation. These results suggest that preferential infection of macrophages with an M2-like phenotype limits T cell-mediated protection against Mtb. Vaccine development should focus on T cell recognition of Mtb-infected macrophages.

CD4 T cells were initially described as helper cells that promote either the cellular immune response (Th1 cells) or the humoral immune response (Th2 cells). Since then, a plethora of functionally distinct helper and regulatory CD4 T cell subsets have been described. CD4 T cells with cytotoxic function were first described in the setting of viral infections and autoimmunity, and more recently in cancer and gut dysbiosis. Regulatory CD4 T cell subsets such as Tregs and T-regulatory type 1 (Tr1) cells have also been shown to have cytotoxic potential. Indeed, Tr1 cells have been shown to be important for maintenance of stem cell niches in the bone marrow and the gut. This review will provide an overview of cytotoxic CD4 T cell development, and discuss the role of inflammatory and Tr1-like cytotoxic CD4 T cells in maintenance of intestinal stem cells and in anti-cancer immune responses.

Venom immunotherapy (VIT) represents a potential therapeutic approach for the management of venom allergies, aiming to modify the immune response to venom allergens and enhance its precision. Previous studies have demonstrated that VIT induces a shift in T helper cell responses from Th2 to Th1, characterized by the production of IL-2 and interferon-gamma by CD4+ and CD8+ cells. In order to explore long-term pathways following VIT treatment and verify potential new outcomes, the serum concentrations of 30 cytokines were assessed in a cohort of 61 patients (18 control, 43 study group) exhibiting hypersensitivity to wasp venom. Cytokine levels were measured at 0, 2, 6, and 24 weeks after the initiation phase of VIT in the study group. The present study found no significant alterations in the levels of IL-2 and IFN-γ in the peripheral blood following VIT. However, a noteworthy finding was the substantial increase in the concentration of IL-12, a cytokine capable of promoting the differentiation of Th0 cells into Th1 cells. This observation supports the involvement of the Th1 pathway in the desensitization process induced by VIT. Additionally, the study revealed a significant rise in the levels of IL-9 and TGF-β after VIT. These cytokines may play a role in the generation of inducible regulatory T (Treg) cells, indicating their potential importance in the immune response to venom allergens and the desensitization process associated with VIT. Nevertheless, further investigations are required to comprehend the underlying mechanisms driving the VIT process comprehensively.

Interleukin-10 (IL-10) is a pleiotropic cytokine that has a fundamental role in modulating inflammation and in maintaining cell homeostasis. It primarily acts as an anti-inflammatory cytokine, protecting the body from an uncontrolled immune response, mostly through the Jak1/Tyk2 and STAT3 signaling pathway. On the other hand, IL-10 can also have immunostimulating functions under certain conditions. Given the pivotal role of IL-10 in immune modulation, this cytokine could have relevant implications in pathologies characterized by hyperinflammatory state, such as cancer, or infectious diseases as in the case of COVID-19 and Post-COVID-19 syndrome. Recent evidence proposed IL-10 as a predictor of severity and mortality for patients with acute or post-acute SARS-CoV-2 infection. In this context, IL-10 can act as an endogenous danger signal, released by tissues undergoing damage in an attempt to protect the organism from harmful hyperinflammation. Pharmacological strategies aimed to potentiate or restore IL-10 immunomodulatory action may represent novel promising avenues to counteract cytokine storm arising from hyperinflammation and effectively mitigate severe complications. Natural bioactive compounds, derived from terrestrial or marine photosynthetic organisms and able to increase IL-10 expression, could represent a useful prevention strategy to curb inflammation through IL-10 elevation and will be discussed here. However, the multifaceted nature of IL-10 has to be taken into account in the attempts to modulate its levels.

The expression of MHC-II and CD86 on the surface of antigen-presenting cells (APCs) must be tightly regulated to foster antigen-specific CD4 T-cell activation and to prevent autoimmunity. Surface expression of these proteins is regulated by their dynamic ubiquitination by the E3 ubiquitin ligase March-I. March-I promotes turnover of peptide-MHC-II complexes on resting APCs and termination of March-I expression promotes MHC-II and CD86 surface stability. In this review, we will highlight recent studies examining March-I function in both normal and pathological conditions.

Visceral leishmaniasis (VL), a vector-borne disease, is caused by an obligate intramacrophage, kinetoplastid protozoan parasite of the genus Leishmania. Globally, VL is construed of diversity and complexity concerned with high fatality in tropics, subtropics, and Mediterranean regions with ~50,000-90,000 new cases annually. Factors such as the unavailability of licensed vaccine(s), insubstantial measures to control vectors, and unrestrained surge of drug-resistant parasites and HIV-VL co-infections lead to difficulty in VL treatment and control. Furthermore, VL treatment, which encompasses several problems including limited efficacy, emanation of drug-resistant parasites, exorbitant therapy, and exigency of hospitalization until the completion of treatment, further exacerbates disease severity. Therefore, there is an urgent need for the development of safe and efficacious therapies to control and eliminate this devastating disease. In such a scenario, biotherapy/immunotherapy against VL can become an alternative strategy with limited side effects and no or nominal chance of drug resistance. An extensive understanding of pathogenesis and immunological events that ensue during VL infection is vital for the development of immunotherapeutic strategies against VL. Immunotherapy alone or in combination with standard anti-leishmanial chemotherapeutic agents (immunochemotherapy) has shown better therapeutic outcomes in preclinical studies. This review extensively addresses VL treatment with an emphasis on immunotherapy or immunochemotherapeutic strategies to improve therapeutic outcomes as an alternative to conventional chemotherapy.

Glioblastoma remains as the most common and aggressive malignant brain tumor, standing with a poor prognosis and treatment prospective. Despite the aggressive standard care, such as surgical resection and chemoradiation, median survival rates are low. In this regard, immunotherapeutic strategies aim to become more attractive for glioblastoma, considering its recent advances and approaches. In this review, we provide an overview of the current status and progress in immunotherapy for glioblastoma, going through the fundamental knowledge on immune targeting to promising strategies, such as Chimeric antigen receptor T-Cell therapy, immune checkpoint inhibitors, cytokine-based treatment, oncolytic virus and vaccine-based techniques. At last, it is discussed innovative methods to overcome diverse challenges, and future perspectives in this area.

Gestational diabetes mellitus (GDM) is the most frequent metabolic alteration in pregnancy. Several abnormalities in visceral adipose tissue (VAT) have been described as part of its pathophysiology including hypertrophy, inflammation and altered lipid metabolism. Farnesoid X receptor (FXR) is involved in adipocyte physiology and inflammation, so its expression may correlate with the expression of tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), lipoprotein lipase (LPL), and two fatty acid transporters (SLC27A2, and SLC27A4).

To compare the FXR, LPL, SLC27A2, SLC27A4, TNF-α, and IL-10 mRNA expression in VAT between women with GDM and healthy pregnant (HP) women. Secondarily, to evaluate the potential correlation between these expression levels.

Cross-sectional study of 50 GDM and 50 HP women. Conventional biochemical tests were performed and relative mRNA expression in VAT was measured by RT-qPCR.

Gene expression levels of FXR and IL-10 were lower, whereas those of LPL, as well as the TNF-α/IL-10 ratio, were higher in women with GDM compared to HP. Pre-pregnancy BMI was the main significant independent variable for FXR levels in VAT from women with GDM. In all women, LPL expression levels correlated positively with those of SLC27A2. Only in women with GDM, IL-10 expression levels correlated negatively with those of SLC27A2, and SLC27A4.

GDM is associated with decreased expression of FXR and IL-10 and increased expression of LPL, as well as a higher TNF/IL-10 ratio in VAT. These results suggest increased lipid storage and pro-inflammatory state indicating VAT dysfunction in this metabolic disorder.

Canine distemper virus (CDV) is the etiological agent of severe disease in domestic and wild carnivores. Clinical diagnosis of CDV is challenging because of its similarity to other canine respiratory and intestinal diseases. We aimed to determine certain cytokine (interleukin [IL]-1β, IL-2, IL-4, IL-6, IL-10, and tumor necrosis factor-α [TNF-α]), interferon (IFN)-γ, canine serum amyloid A (SAA), and canine citrulline (CIT) levels for the first time in CDV-positive dogs. For this purpose, 10 CDV-positive dogs with compatible clinical findings (i.e., neurological symptoms such as tremors and myoclonus, ocular and nasal discharge, and wheezing) and 10 healthy dogs based on the clinical examinations and rapid test results were enrolled. It was observed that the CIT, INF-γ, IL-1β, IL-2, IL-6, and TNF-α levels were significantly decreased in the CDV-positive dogs than that of the healthy ones (P<0.05). As a result, it was observed that CDV causes immunosuppression and accordingly, the inflammatory response might cause decreased cytokine and acute-phase protein synthesis. Therefore, it was concluded that further investigation of inflammatory pathways and CIT interactions may provide crucial clinical information at different stages of CDV, and aforementioned parameters may serve as important biomarkers for CDV in terms of demonstrating the presence of immunosuppression.

Cellular communication mediated by cytokines is an important mechanism dictating immune responses, their cross talk and final immune output. Cytokines play a major role in dictating the immune outcome to cancer by regulating the events of development, differentiation and activation of innate immune cells. Cytokines are pleiotropic in nature, hence understanding their role individually or as member of network cytokines is critical to delineate their role in tumour immunity. Tumour systemically manipulates the immune system to evade and escape immune recognition for their uncontrollable growth and metastasis. The developing tumour comprise a large and diverse set of myeloid cells which are vulnerable to manipulation by the tumour-microenvironment. The innate immune cells of the monocytic lineage skew the fate of the adaptive immune cells and thus dictating cancer elimination or progression. Targeting cells at tumour cite is preposterous owing to their tight network, poor reach and abundance of immunosuppressive mechanisms. Monocytic lineage-derived cytokines (monokines) play crucial role in tumour regression or progression by either directly killing the tumour cells with TNFα or promoting its growth by TGFβ. In addition, the monokines like IL-12, IL-1β, IL-6, IL-10 and TGFβ direct the adaptive immune cells to secrete anti-tumour cytokines, TNFα, IFNγ, perforin and granzyme or pro-tumour cytokines, IL-10 and TGFβ. In this review, we elucidate the roles of monokines in dictating the fate of tumour by regulating responses at various stages of generation, differentiation and activation of immune cells along with the extensive cross talk. We have attempted to delineate the synergy and antagonism of major monokines among themselves or with tumour-derived or adaptive immune cytokines. The review provides an update on the possibilities of placing monokines to potential practical use as cytokine therapy against cancer.

Esophageal adenocarcinoma (EAC) develops from a chronic inflammatory environment across four stages: intestinal metaplasia, known as Barrett's esophagus, low- and high-grade dysplasia, and adenocarcinoma. Although the genomic characteristics of this progression have been well defined via large-scale DNA sequencing, the dynamics of various immune cell subsets and their spatial interactions in their tumor microenvironment remain unclear. Here, we applied a sequential multiplex immunohistochemistry (mIHC) platform with computational image analysis pipelines that allow for the detection of 10 biomarkers in one formalin-fixed paraffin-embedded (FFPE) tissue section. Using this platform and quantitative image analytics, we studied changes in the immune landscape during disease progression based on 40 normal and diseased areas from endoscopic mucosal resection specimens of chemotherapy treatment- naïve patients, including normal esophagus, metaplasia, low- and high-grade dysplasia, and adenocarcinoma. The results revealed a steady increase of FOXP3+ T regulatory cells and a CD163+ myelomonocytic cell subset. In parallel to the manual gating strategy applied for cell phenotyping, we also adopted a sparse subspace clustering (SSC) algorithm allowing the automated cell phenotyping of mIHC-based single-cell data. The algorithm successfully identified comparable cell types, along with significantly enriched FOXP3 T regulatory cells and CD163+ myelomonocytic cells as found in manual gating. In addition, SCC identified a new CSF1R+CD1C+ myeloid lineage, which not only was previously unknown in this disease but also increases with advancing disease stages. This study revealed immune dynamics in EAC progression and highlighted the potential application of a new multiplex imaging platform, combined with computational image analysis on routine clinical FFPE sections, to investigate complex immune populations in tumor ecosystems.

Interleukin-10 (IL-10) is an immunosuppressive cytokine that signals through STAT3 to regulate T follicular helper (Tfh) cell differentiation and germinal center formation. In SIV-infected macaques, levels of IL-10 in plasma and lymph nodes (LNs) were induced by infection and not normalized with antiretroviral therapy (ART). During chronic infection, plasma IL-10 and transcriptomic signatures of IL-10 signaling were correlated with the cell-associated SIV-DNA content within LN CD4+ memory subsets, including Tfh cells, and predicted the frequency of CD4+ Tfh cells and their cell-associated SIV-DNA content during ART, respectively. In ART-treated rhesus macaques, cells harboring SIV-DNA by DNAscope were preferentially found in the LN B cell follicle in proximity to IL-10. Finally, we demonstrated that the in vivo neutralization of soluble IL-10 in ART-treated, SIV-infected macaques reduced B cell follicle maintenance and, by extension, LN memory CD4+ T cells, including Tfh cells and those expressing PD-1 and CTLA-4. Thus, these data support a role for IL-10 in maintaining a pool of target cells in lymphoid tissue that serve as a niche for viral persistence. Targeting IL-10 signaling to impair CD4+ T cell survival and improve antiviral immune responses may represent a novel approach to limit viral persistence in ART-suppressed people living with HIV.

The M1 macrophage is characterized by enhanced pro-inflammatory cytokines production, whereas macrophage (M2) has anti-inflammatory features. Macrophage polarization as a therapeutic target for controlling immune responses could be performed by gene transduction to control the regulation of exaggerated innate/adaptive immune responses.

Macrophages were prepared from THP-1 cell line and human monocytes that were transduced with (Membrane-Associated RING-CH-type finger) MARCH-1 viral lentivector produced in HEK-293T cells. RT-PCR and Western blotting confirmed MARCH-1 gene transduction. Cytokine production, CD markers assay, macrophage phagocytosis potential activity and mixed leukocyte reaction (MLR) with CFSE were performed for M1/M2 plasticity.

The mean fluorescent intensity of HLA-DR and CD64 expression reduced in MARCH-1+ transduced macrophage population. However, CD206 and CD163 expression increased in these macrophages. The concentrations of IL-6, TNF-α and iNOS were decreased in MARCH-1 transduced cells, and TGF-β production showed an augmentation in concentration. Western blotting and real-time PCR measurement confirmed that the expression levels of MARCH-1 protein and arginase-1 enzyme were increased in transduced macrophages.

The anti-inflammatory features of MARCH-1 revealed the reduced levels of pro-inflammatory factors and maintained M2 phenotype characterized by high levels of scavenger receptors. Therefore, targeting MARCH-1 in monocytes/macrophages could represent a new autologous cell-based therapies strategy for inflammatory conditions.

Triple negative breast cancer (TNBC) is an aggressive breast cancer for which there is currently no targeted therapy. Tumor-infiltrating B-cells (TIB) have been observed in tumor tissues of TNBC patients, but their functional role is unclear. IgG4 is one of four antibody subclasses of IgG expressed and secreted by B cells. Unlike other IgG isotypes, IgG4 has an immunosuppressive function and is induced by Th2-type cytokines. In cancers such as melanoma, IgG4 has been linked with advanced disease and poor patient survival. Therefore, we sought to determine if IgG4 + B cells are present and determine the mechanisms driving isotype switching in TNBC.

We performed co-culture assays to examine expression of Th2 cytokines by TNBC cells with and without the presence of B cells. We also performed in vitro class switching experiments with peripheral B cells with and without co-culture with TNBC cells in the presence or absence of an IL-10 blocking antibody. We examined expression of CD20+ TIB, IgG4 and Th2 cytokines by immunohistochemistry in 152 TNBC samples. Statistical analysis was done using Log-Rank and Cox-proportional hazards tests.

Our findings indicate that B cells interact with TNBC to drive chronic inflammatory responses through increased expression of inflammatory cytokines including the TH2 cytokines IL-4 and IL-10. In vitro class switching studies show that interactions between TNBC cell lines and B cells drive isotype switching to the IgG4 isotype in an IL-10 dependent manner. In patient tissues, expression of IgG4 correlates with CD20 and tumor expression of IL-10. Both IgG4 and tumor IL-10 are associated to shorter recurrence free survival (RFS) and overall survival (OS) in TNBC. In a multi-variant analysis, IL-10 was associated with poor outcomes indicating that tumor IL-10 may drive immune escape.

These findings indicate that interactions between TIB and TNBC results in activation of chronic inflammatory signals such as IL-10 and IL-4 that drive class switching to an IgG4 + subtype which may suppress antibody driven immune responses. The presence of IgG4 + B cells may serve as a biomarker for poor prognosis.