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Regulatory T cells (Tregs) could maintain the characteristics of stem cells and inhibit the differentiation of normal hematopoietic stem/progenitor cells. Recent studies have shown that Tregs, as an important component of acute myeloid leukemia (AML) microenvironments, can help AML cells to evade immune surveillance. However, their function in directly regulating the stemness of AML cells remains elusive. In this study, the increased stemness of AML cells promoted by Tregs was verified in vitro and in vivo. The cytokines released by Tregs were explored, the highly expressed anti-inflammatory cytokine IL10 was found, which could promote the stemness of AML cells through the activation of PI3K/AKT signal pathway. Moreover, disrupting the IL10/IL10R/PI3K/AKT signal in AML/ETO c-kitmut (A/Ec) leukemia mice could prolong the mice survival and reduce the stemness of A/Ec leukemia cells. Finally, it was confirmed in patient samples that the proportion of Tregs to leukemia stem cells (LSCs) was positively correlated, and in CD34+ primary AML cells, the activation of PI3K/AKT was stronger in patients with high Tregs’ infiltration. After rhIL10 treatment, primary AML cells showed increased activation of PI3K/AKT signaling. Therefore, blocking the interaction between Tregs and AML cells may be a new approach to target LSCs in AML treatment.

Recently, it was found that microglia regulated synaptic remodeling of the developing brain, but their mechanisms have not been well understood. In this study, the action of microglia on neuronal synapse formation was investigated, and the primary target of microglial processes was discovered. When the developing microglia were applied to cultured hippocampal neurons without direct contact, the numbers of dendritic spines and excitatory and inhibitory synapses significantly increased. In order to find out the main factor for synaptic formation, the effects of cytokines released from microglia were examined. When recombinant proteins of cytokines were applied to neuronal culture media, interleukin 10 increased the numbers of dendritic spines in addition to excitatory and inhibitory synapses. Interestingly, without external stimuli, the amount of interleukin 10 released from the intact microglia appeared to be sufficient for the induction of synaptic formation. The neutralizing antibodies of interleukin 10 receptors attenuated the induction of the synaptic formation by microglia. The expression of interleukin 10 receptor was newly found in the hippocampal neurons of early developmental stage. When interleukin 10 receptors on the hippocampal neurons were knocked down with specific shRNA, the induction of synaptic formation by microglia and interleukin 10 disappeared. Pretreatment with lipopolysaccharide inhibited microglia from inducing synaptic formation, and interleukin 1β antagonized the induction of synaptic formation by interleukin 10. In conclusion, the developing microglia regulated synaptic functions and neuronal development through the interactions of the interleukin 10 released from the microglia with interleukin 10 receptors expressed on the hippocampal neurons.

Background Lymphocytes have dichotomous functions in ischemic stroke. Regulatory T cells are protective, while IL-17A from innate lymphocytes promotes the infarct growth. With recent advances of T cell-subtype specific transgenic mouse models it now has become possible to study the complex interplay of T cell subpopulations in ischemic stroke. Methods In a murine model of experimental stroke we analyzed the effects of IL-10 on the functional outcome for up to 14 days post-ischemia and defined the source of IL-10 in ischemic brains based on immunohistochemistry, flow cytometry, and bone-marrow chimeric mice. We used neutralizing IL-17A antibodies, intrathecal IL-10 injections, and transgenic mouse models which harbor a deletion of the IL-10R on distinct T cell subpopulations to further explore the interplay between IL-10 and IL-17A pathways in the ischemic brain. Results We demonstrate that IL-10 deficient mice exhibit significantly increased infarct sizes on days 3 and 7 and enlarged brain atrophy and impaired neurological outcome on day 14 following tMCAO. In ischemic brains IL-10 producing immune cells included regulatory T cells, macrophages, and microglia. Neutralization of IL-17A following stroke reversed the worse outcome in IL-10 deficient mice and intracerebral treatment with recombinant IL-10 revealed that IL-10 controlled IL-17A positive lymphocytes in ischemic brains. Importantly, IL-10 acted differentially on αβ and γδ T cells. IL-17A producing CD4 + αβ T cells were directly controlled via their IL-10-receptor (IL-10R), whereas IL-10 by itself had no direct effect on the IL-17A production in γδ T cells. The control of the IL-17A production in γδ T cells depended on an intact IL10R signaling in regulatory T cells (Tregs). Conclusions Taken together, our data indicate a key function of IL-10 in restricting the detrimental IL-17A-signaling in stroke and further supports that IL-17A is a therapeutic opportunity for stroke treatment.

Macrophages are a heterogeneous population of mononuclear phagocytes abundantly distributed throughout the intestinal compartments that adapt to microenvironmental specific cues. In adult mice, the majority of intestinal macrophages exhibit a mature phenotype and are derived from blood monocytes. In the steady-state, replenishment of these cells is reduced in the absence of the chemokine receptor CCR2. Within the intestine of mice with colitis, there is a marked increase in the accumulation of immature macrophages that demonstrate an inflammatory phenotype. Here, we asked whether CCR2 is necessary for the development of colitis in mice lacking the receptor for IL10. We compared the development of intestinal inflammation in mice lacking IL10RA or both IL10RA and CCR2. The absence of CCR2 interfered with the accumulation of immature macrophages in IL10R-deficient mice, including a novel population of rounded submucosal Iba1 + cells, and reduced the severity of colitis in these mice. In contrast, the absence of CCR2 did not reduce the augmented inflammatory gene expression observed in mature intestinal macrophages isolated from mice lacking IL10RA. These data suggest that both newly recruited CCR2-dependent immature macrophages and CCR2-independent residual mature macrophages contribute to the development of intestinal inflammation observed in IL10R-deficient mice.

Infection-induced T cell responses must be properly tempered and terminated to prevent immuno-pathology. Using transgenic mice, we demonstrate that T cell intrinsic STAT1 signaling is required to curb inflammation during acute infection with Toxoplasma gondii . Specifically, we report that mice lacking STAT1 selectively in T cells expel parasites but ultimately succumb to lethal immuno-pathology characterized by aberrant Th1-type responses with reduced IL-10 and increased IL-13 production. We also find that, unlike STAT1, STAT3 is not required for induction of IL-10 or suppression of IL-13 during acute toxoplasmosis. Each of these findings was confirmed in vitro and ChIP-seq data mining showed that STAT1 and STAT3 co-localize at the Il10 locus, as well as loci encoding other transcription factors that regulate IL-10 production, most notably Maf and Irf4 . These data advance basic understanding of how infection-induced T cell responses are managed to prevent immuno-pathology and provide specific insights on the anti-inflammatory properties of STAT1, highlighting its role in shaping the character of Th1-type responses.

In mammals, M cells can take up antigens through mucosal surfaces of the gut and the respiratory tract. Since M cells are deficient of lysosomes and phagosomes, the antigens are directly delivered to the mucosa-associated lymphoid tissue (MALT) without degradation. In teleost fish, the entire body surface (gills, skin, and intestinal system) is covered by mucus; however, specific antigen-sampling cells have not yet been identified in their mucosal tissues. Here, we show that two phenotypes of antigen-sampling cells take up antigens through epithelial surfaces of the rainbow trout gill. One phenotype of antigen-sampling cells has features of monocyte/macrophage/dendritic cell-type cells; they have large vacuoles in the cytoplasm and express PTPRC (CD45), CD83, IL-1β, and IL-12p40b. The second phenotype exhibits similar characteristics to mammalian M cells; the corresponding cells bind the lectin UEA-1 but not WGA and show expression of M cell marker gene Anxa5. In contrast to mammalian M cells, teleost M-type cells were found to exhibit small vacuoles in their cytoplasm and to express almost all genes related to the \"phagosome\", \"lysosome,\" and \"antigen processing and presentation\" pathways. Furthermore, MHC class II was constitutively expressed on a fraction of M-type cells, and this expression was significantly increased after antigen uptake, suggesting that the MHC class II is inducible by antigen stimulation. Here, we suggest that teleost M-type cells play a role in the phylogenetically primitive teleost immune system, similar to bona-fide M cells. In addition, the presence of MHC class II expression suggests an additional role in antigen presentation in the gills, which are an organ with high T cell abundance, especially in interbranchial lymphoid tissue. The present results suggest an unconventional antigen presentation mechanism in the primitive mucosal immune system of teleosts, which generally lack highly organized lymphoid tissues. Moreover, the results of this work may be valuable for the development of mucosal vaccines that specifically target M-type cells; mucosal vaccines significantly reduce working costs and the stress that is usually induced by vaccination via injection of individual fish.

The tumor microenvironment (TME) provides a conducive environment for the growth and survival of tumors. Negative factors present in TME, such as IL-10, may limit the effectiveness of cellular vaccines based on dendritic cells, therefore, it is important to control its effect. The influence of IL-10 on immune cells can be abolished e.g., by using antibodies against the receptor for this cytokine - anti-IL-10R. Furthermore, the anticancer activity of cellular vaccines can be enhanced by modifying them to produce proinflammatory cytokines, such as IL-12, IL-15 or IL-18. Additionally, an immunomodulatory dose of methotrexate and hydroxyethyl starch (HES-MTX) nanoconjugate may stimulate effector immune cells and eliminate regulatory T cells, which should enhance the antitumor action of immunotherapy based on DC vaccines. The main aim of our study was to determine whether the HES-MTX administered before immunotherapy with anti-IL-10R antibodies would change the effect of vaccines based on dendritic cells overproducing IL-12, IL-15, or IL-18. The activity of modified DCs was checked in two therapeutic protocols - immunotherapy with the addition of anti-IL10R antibodies and chemoimmunotherapy with HES-MTX and anti-IL10R antibodies. The inhibition of tumor growth and the effectiveness of the therapy in inducing a specific antitumor response were determined by analyzing lymphoid and myeloid cell populations in tumor nodules, and the activity of restimulated splenocytes. Using the HES-MTX nanoconjugate before immunotherapy based on multiple administrations of anti-IL-10R antibodies and cellular vaccines capable of overproducing proinflammatory cytokines IL-12, IL-15 or IL-18 created optimal conditions for the effective action of these vaccines in murine colon carcinoma MC38 model. The applied chemoimmunotherapy caused the highest inhibition of tumor growth in the group receiving DC/IL-15/IL-15Rα/TAg + DC/IL-18/TAg at the level of 72.4%. The use of cellular vaccines resulted in cytotoxic activity increase in both immuno- or chemoimmunotherapy. However, the greatest potential was observed both in tumor tissue and splenocytes obtained from mice receiving two- or three-component vaccines in the course of combined application. Thus, the designed treatment schedule may be promising in anticancer therapy.

Immune checkpoint inhibitors (ICIs) brought about a major paradigm shift in non-small cell lung cancer (NSCLC) treatment. However, the use of ICIs is related to an unforeseeable pattern of immune-related adverse events (irAEs). Hence, more precise biomarkers are needed to predict the incidence of irAEs to prevent overtreatment of ICIs and decrease occurrences of irAEs. This study was designed to identify capable clinical features and plasma inflammatory factors for predicting irAEs. A total of 67 patients who received ICI monotherapy or ICI-based combination therapy were retrospectively identified. Clinical characteristics and plasma inflammatory cytokines were collected and analyzed to screen potential biological markers associated with irAEs. The chi-square test, Fisher's test, and the Mann-Whitney U test were performed for the primary analysis. The optimal cutoff value was determined by a receiver operating characteristic (ROC) curve. Univariate and multivariate logistic regression models were used to identify risk factors of irAEs. Univariate and multivariate Cox proportional hazards were also performed. Out of 67 patients, 40 (59.7%) experienced irAEs, and 7 (10.4%) experienced severe adverse events (grade ≥ 3). Among these analyzed immune profile biomarkers, only interleukin-10 (IL-10) was related to the risk of irAEs. A high baseline IL-10 plasma level (odds ratio (OR) = 5.318, 95% CI 1.174-24.081, p = 0.030) was found to be a tremendous and independent risk factor for the development of irAEs. Also, for the dynamic analysis, upregulation of IL-10 after one cycle of ICI treatment was positively related to the occurrence of irAEs (OR = 5.712, 95% CI 1.088-29.993, p = 0.039). When pneumonitis, the most common irAEs, was analyzed, only baseline high-expression IL-10 was accompanied with the incidence of pneumonitis (OR = 9.969, 95% CI 1.144-86.843, p = 0.037). Baseline and dynamic IL-10 plasma levels are tremendously and independently related to higher risk in the development of irAEs and could be utilized for medical practice to monitor adverse events in patients with ICI treatment.

Infants with defects in the interleukin 10 receptor (IL10R) develop very early onset inflammatory bowel disease. Whether IL10R regulates lamina propria macrophage function during infant development in mice and whether macrophage-intrinsic IL10R signaling is required to prevent colitis in infancy is unknown. Here we show that although signs of colitis are absent in IL10R-deficient mice during the first two weeks of life, intestinal inflammation and macrophage dysfunction begin during the third week of life, concomitant with weaning and accompanying diversification of the intestinal microbiota. However, IL10R did not directly regulate the microbial ecology during infant development. Interestingly, macrophage depletion with clodronate inhibited the development of colitis, while the absence of IL10R specifically on macrophages sensitized infant mice to the development of colitis. These results indicate that IL10R-mediated regulation of macrophage function during the early postnatal period is indispensable for preventing the development of murine colitis. Inflammation is an immune response that helps the body to repair damaged tissues and defend itself against bacteria and other harmful microbes. Immune cells called macrophages stimulate inflammation when they detect bacteria and other microbes. However, the strength of the inflammatory response is tightly controlled to prevent too much inflammation when it is not necessary. There is evidence that an inability to control the activity of macrophages can lead to excessive inflammation that can in itself cause injury. Inflammatory bowel diseases, including Crohn’s disease and ulcerative colitis, occur when the intestine becomes inflamed in response to the bacteria that normally live there. Most patients with these diseases first present symptoms as young adults, but in rare cases the symptoms appear during infancy. Some patients who develop symptoms early in life carry a mutation in a gene encoding IL10R, a receptor protein that normally inhibits the ability of macrophages to cause inflammation. However, it was not known exactly when the inflammation begins in infants. Mice are often used in research as models of human health and disease. Redhu et al. investigated the role of IL10R in the intestines of infant mice. These experiments showed that the intestines of mutant mice that lacked the IL10R protein became inflamed as they were weaned from breast milk to a solid diet. This inflammation was accompanied by a greater increase in the number of actively recruited macrophages in the intestine of mutant mice compared to normal mice. Further experiments revealed that macrophages in the mutant mice activate many genes involved in inflammation. The transition from breast milk to a solid diet is accompanied by large increases in intestinal bacteria. Treating the mice with antibiotics decreased the number of bacteria in the intestines and reduced the level of inflammation, as did treating the mice with a compound that killed macrophages. The findings of Redhu et al. suggest that IL10R prevents macrophages from causing inflammation when infant mice are weaned. This, in turn, suggests that treatments that modify intestinal macrophages, as well as bacteria, could help infants that have, or are at risk of developing inflammatory bowel disease. In the longer-term, these findings might also aid the development of new treatments for older patients with inflammatory bowel diseases.

The claudin protein family plays key roles in maintaining normal structure and function of epithelial and endothelial tight junctions. While several prior studies have addressed the expression of claudin in adipocytes that do not form tight junctions, here we demonstrate that CLDN5 is selectively expressed in non-thermogenic adipocytes within adipose tissue. Ablation of CLDN5 in adipocyte impairs thermogenesis and energy expenditure. CLDN5 deficiency also significantly increases diet-induced fat mass in mice, accompanied with glucose intolerance and insulin resistance. Mechanistically, CLDN5 affects the subcellular localization of Y-box protein 3, which directly regulates IL10 expression via binding to its promoter and specific sites in 3′-untranslated region, thereby acts in a paracrine manner to signal through IL10R in neighbouring thermogenic adipocytes. These findings expand our understanding about location and function of the extra-tight junction claudin proteins and provide molecular insights into signaling mechanisms underlying adipose thermogenesis that could inform future therapy. Claudin proteins maintain epithelial and endothelial tight junctions, but their functions in adipocytes lacking such junctions remain unclear. Here, the authors show that claudin-5 present in non-thermogenic adipocytes regulates thermogenesis and energy expenditure by modulating IL-10 secretion.