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Alcohol-associated liver disease (ALD) encompasses a wide range of pathologies from simple steatosis to cirrhosis and hepatocellular carcinoma and is a global health problem. Currently, there are no effective pharmacological treatments for ALD. We have previously demonstrated that aging exacerbates the pathogenesis of ALD, but the underlying mechanisms are still poorly understood. Cellular repressor of E1A-stimulated genes 1 protein (CREG1) is a recently identified small glycoprotein that has been implicated in aging process by promoting cellular senescence and activating stress kinases. Thus, the current study aimed to explore the role of aging associated CREG1 in ALD pathogenesis and CREG1 as a potential therapeutic target. Hepatic and serum CREG1 protein levels were elevated in ALD patients. Elevation of hepatic CREG1 protein and mRNA was also observed in a mouse model of Gao-binge alcohol feeding. Genetic deletion of the

Background Natural killer (NK) cells typically function as frontline lymphocytes against cancer although little is known about their engagement in non–small cell lung cancer (NSCLC). This study compared the performance and activity of NK cells and their subsets in the peripheral blood of NSCLC sufferers and healthy participants. Methods In total, 67 healthy controls (40 men; 59.7%) and 56 patients with NSCLC (35 men; 62.5%) were included (mean age, 66.6 years). Flow cytometry identified NK cells and their subpopulations in external blood, and the total number, proportion, activity, surface activating and inhibitory receptor expression levels were determined. Results NK cell surface receptors CD107a, IFN-γ, and TNF-α activity were markedly reduced in lung cancer patients compared to healthy controls. The number and ratio of NK cells within the lymphocyte population were decreased in patients. The concentration of the inhibitory receptors TIGIT, TIM-3, CD96, PD-1, and Siglec-7 were increased in patients, whereas the expression level of the activating receptor NKP30 was decreased. Moreover, the expression levels of IFN-γ, TIGIT, CD96, PD-1, and TIM-3 were correlated with the clinical phase of NSCLC.Conclusions NSCLC patients have decreased number and function of external blood NK cells, and the proportion of most of the inhibitory receptors assessed on NK cells in this study increased as the disease progressed. These findings suggest that surface receptors from NK cells are likely to be involved in the evolution of NSCLC.

The inflammasome has been linked to diverse inflammatory and metabolic diseases, and tight control of inflammasome activation is necessary to avoid excessive inflammation. Kynurenic acid (KA) is a tryptophan metabolite in the kynurenine pathway. However, the roles and mechanisms of the regulation of inflammasome activation by KA have not yet been fully elucidated. Here, we found that KA suppressed caspase-1 activation and IL-1β production in macrophages by specifically inhibiting canonical and noncanonical activation of the NLRP3 inflammasome. Mechanistically, KA reduced calcium mobilization through G-protein receptor 35 (GPR35), resulting in reduced mitochondrial damage and decreased mtROS production, thus blocking NLRP3 inflammasome assembly and activation. Importantly, KA prevented lipopolysaccharide-induced systemic inflammation, monosodium urate-induced peritoneal inflammation, and high-fat diet-induced metabolic disorder. Thus, KA ameliorated inflammation and metabolic disorders by blocking calcium mobilization-mediated NLRP3 inflammasome activation

Natural killer (NK) cells are regarded as the host's first line of defense against viral infection. Moreover, the involvement of NK cells in chronic obstructive pulmonary disease (COPD) has been documented. However, the specific mechanism and biological changes of NK cells in COPD development have not been determined. In this study, we extracted NK cells from the peripheral blood of 18 COPD patients who were recovering from an acute exacerbation and 45 healthy donors (HDs), then we labeled NK cells with different antibodies and analyzed with flow cytometry. The data showed that the frequencies of total NK cells in the peripheral blood of COPD patients were lower compared with HDs. Moreover, the inhibitory receptors on NK cells expressed higher levels and the expression of activating receptors were generally low. Importantly, both the expression levels of CD96 in NK cells and the frequencies of CD96

Objective Natural killer (NK) cells have gained considerable attention due to their potential in treating "cold tumors," and are therefore considered as one of the new strategies for curing cancer, by using worldwide development of their new possibilities and interventions with NK cell-related therapeutic products. Methods We constructed a trispecific killer engager (TriKE) consisting of anti-CD16, IL-15, and anti-CD19. This TriKE was designed to attract CD19+ tumor cells to CD16+ NK cells, whereas IL-15 sustained the proliferation, development, and survival of NK cells. Results Treatment with 161519 TriKE in the presence of CD19+ targets upregulated expression of CD69, CD107a, TRAIL, IFN-γ, and TNF-α in NK cells, and significantly improved the proliferation and cytotoxicity of NK cells. NK cells "armed" with 161519 TriKE showed stronger cytolysis against CD19+ targets compared with that of "unarmed" NK cells. A preclinical model of B-cell lymphoma in human peripheral blood mononuclear cell-reconstituted xenograft mice showed significant inhibition of tumor growth and prolonged overall survival after treatment with 161519 TriKE, when compared with that in control mice or mice treated with 1619 BiKE. Combined use of IL-2 was a more effective treatment with 1619 BiKE, when compared with that using 161519 TriKE. Conclusions The newly generated 161519 TriKE enhanced the proliferation, activation, cytokine secretion, and cytotoxicity of NK cells in the presence of CD19+ tumor cells. The 161519 TriKE aided inhibition of tumor growth and prolonged the overall survival of murine xenografts, and could be used to treat CD19-positive cancers.

Summary Major histocompatibility complex class I (MHC-I)-dependent inhibitory receptors on natural killer (NK) cells have been found to contribute to NK cell dysfunction in hepatocellular carcinoma (HCC). However, the roles of MHC-I-independent inhibitory receptors on NK cells in HCC remain poorly defined. In this study, we analyzed the expression of the MHC-I-independent inhibitory receptors sialic acid-binding immunoglobulin-like lectin (Siglec)-7 and Siglec-9 on NK cells by analyzing the peripheral blood of 35 HCC patients and 63 healthy donors. We observed that HCC patients had lower frequencies and total numbers of NK cells in the peripheral blood. Importantly, both the expression levels of Siglec-7 on NK cells and the frequencies of Siglec-7+ NK cells were significantly reduced in HCC patients, which was accompanied by a decrease in activating receptor and an increase in inhibitory receptor expression on NK cells. Moreover, Siglec-7+ NK cells expressed higher levels of activating receptors and displayed stronger effector functions, compared with Siglec-7− NK cells. Our findings demonstrate for the first time that reduced Siglec-7 expression predicts NK cell dysfunction in HCC patients, suggesting that Siglec-7 may be a potential marker of functional NK cell subset in HCC patients.

Natural killer (NK) cells play a crucial role in the control of human viral infections but their activity is significantly impaired in patients infected with chronic hepatitis B (CHB). The mechanism that contributes to NK cell dysfunction in CHB needs further elucidation. In this study, we analyzed the expression and function of the novel inhibitory receptor immunoglobulin-like transcript-2 (ILT2) on NK cells from 131 CHB patients and 36 healthy controls. We observed that ILT2 expression on circulating CD56

Although T cell centered immune checkpoint blockade (ICB) therapies have shown unprecedented success in various cancer types, only a minority of patients benefit from these treatments due to the lack of neoantigen burden and exhaustion of tumor-infiltrating immune stimulating cells. Inspired by the crucial role of NK cell based immunity and potential immunostimulating effect of chemotherapeutic drugs, the therapeutic efficiency on tumor inhibition through combination of doxorubicin (DOX) and blockade of TIGIT (T-cell Ig and ITIM domain), a co-inhibitory receptor expressed by both NK and T cells, in a matrix metalloproteinase 2 (MMP-2)-degradable hydrogel was thoroughly evaluated in this study. Due to the distinct release kinetics from destructed framework of hydrogels, the differentially released DOX and anti-TIGIT monoclonal antibody (aTIGIT) molecules could elicit immunogenic tumor microenvironment and reverse the exhaustion of NK and effector T cells to realize not only durable localized tumor inhibition but also systemic and long-lasting immune memory responses. Thus, our work pioneered the union of chemotherapeutic drugs and NK cell centered ICB therapies for activating cascade-like anti-tumor immune responses through eliciting immunogenic tumor microenvironment and boosting both innate and adaptive immunity. This article is protected by copyright. All rights reserved.

CD3+CD56+ NKT-like cells play pivotal roles in the anti-tumor immune defense response. However, little is known regarding circulating NKT-like cells in patients with primary hepatocellular carcinoma (HCC). In the present study, we demonstrate that circulating NKT-like cells in HCC patients are functionally impaired and anti-PD-1 blockade improves their anti-tumor potency. Circulating NKT cells were mainly comprised of CD8+ T cells. The frequencies and absolute counts of circulating NKT-like cells were comparable between HCC patents compared to healthy donors. NKT-like cells in HCC patients were impaired in their production of TNF-α and IFN-γ as well as cytotoxicity. The level of activating receptor NKG2D was significantly decreased on NKT-like cells in HCC patients. In contrast, the expression of inhibitory receptors PD-1, Tim-3, and CTLA-4 were markedly increased on NKT-like cells in HCC patients. Meanwhile, the expression of PD-L1 was also upregulated on NKT-like cells in HCC patients. In detail, PD-1+ NKT-like cells expressed lower levels of NKG2D, higher levels of Tim-3, and CTLA-4, and less IFN-γ when compared with PD-1− NKT-like cells. Importantly, PD-1 blocked with anti-PD-1 antibody effectively improved the effector function of NKT-like cells from HCC patients or healthy donors. Our findings unveil the functional characterization of NKT-like cells in HCC patients and provide the potential targets to improve their function, which might benefit the optimization of HCC immunotherapy.

Natural killer (NK) cells are innate lymphocytes specialized in immune surveillance against tumors and infections. To reach their optimal functional status, NK cells must undergo a process of maturation from immature to mature NK cells. Genetically modified mice, as well as in vivo and in vitro NK cell differentiation assays, have begun to reveal the landscape of the regulatory network involved in NK cell maturation, in which a balance of cytokine signaling pathways leads to an optimal coordination of transcription factor activity. An increased understanding of NK cell maturation will greatly promote the development and application of NK cell-based clinical therapy. Thus, in this review, we summarize the dynamics of NK cell maturation, describe recently identified factors involved in the regulation of the NK cell maturation process, including cytokines and transcription factors, and discuss the importance of NK cell maturation in health and disease.

γδ T cells display unique developmental, distributional, and functional patterns and can rapidly respond to various insults and contribute to diverse diseases. Different subtypes of γδ T cells are produced in the thymus prior to their migration to peripheral tissues. γδ T cells are enriched in the liver and exhibit liver-specific features. Accumulating evidence reveals that γδ T cells play important roles in liver infection, non-alcoholic fatty liver disease, autoimmune hepatitis, liver fibrosis and cirrhosis, and liver cancer and regeneration. In this study, we review the properties of hepatic γδ T cells and summarize the roles of γδ T cells in liver diseases. We believe that determining the properties and functions of γδ T cells in liver diseases enhances our understanding of the pathogenesis of liver diseases and is useful for the design of novel γδ T cell-based therapeutic regimens for liver diseases.

Immune dysfunction is an established risk factor in acute myeloid leukemia (AML). The cytotoxicity of natural killer (NK) cells is greatly impaired in AML, and the profile of NK cell receptors is markedly altered in AML; however, this is not yet well characterized. In this study, we found the downregulation of Siglec-7 could be utilized as a potential marker of NK cell dysfunction in AML. The absolute numbers and percentages of NK cells were declined in the peripheral blood of patients with AML, and the levels of activating receptors NKG2D, NKp46, and NKp30 were reduced in NK cells from patients with AML compared with healthy controls. In contrast, the levels of inhibitory receptors TIM-3, ILT-4, ILT-5, and PD-1 were increased in NK cells from patients with AML. Of note, the level of Siglec-7 in NK cells from patients with AML was significantly lower than that in NK cells from healthy controls, and Siglec-7+ NK cells displayed higher levels of activating receptors and stronger cytotoxicity when compared with Siglec-7- NK cells. Our data indicate that decreased Siglec-7 level may predict NK cell dysfunction in AML, and NK cells may be promising targets of immunotherapy for AML.

Humanized mice are crucially important for preclinical studies. However, the development and potential function of human B cells in chimeras remain unclear. Here, we describe the study of human B cells in NOD/LtSzPrkdcscid/J (NOD/SCID) mice. In this study, we transplanted 1.0×10(5) human CD34(+) cells from umbilical cord blood (UCB) into NOD/SCID mice after pretreatment with anti-asialo GM1 antiserum and sublethal irradiation. Human CD45(+) cells were detected in the peripheral blood of the recipient mice from 6 weeks after transplantation. CD19(+) B cells accounted for the greater part of the CD45(+) cells in the human UCB-chimeric mice, but their maturational stages differed in different organs. Most of the bone marrow (BM) CD19(+) cells were immature IgM(-)IgD(-)CD24(hi)CD38(hi) B cells, whereas the mature CD5(+)IgM(+)IgD(+)CD24(int)CD38(int)CD19(+) B cells were predominantly present in the spleen and peripheral blood. Human immunoglobulin (Ig) M was detected in mouse plasma. The human B cells also secreted human interleukin-10 after stimulation with LPS in vitro. These results show that human CD34(+) cells can differentiate into human B cells in NOD/SCID mice, with development and functions that are similar to those of B cell subsets in humans. The transplantation of human CD34(+) cells into NOD/SCID mice may provide a useful tool to study the development and function of human B cells.

Adenovirus or adenoviral vectors were reported to induce serious liver inflammation in an NK cell–dependent manner, which limits its clinical applicability for liver gene therapy. We tried to develop an efficient liver-directed therapeutic approach to control hepatic NK cell function via simultaneously manipulating multiple immune genes. Based on our previous study, we found that CCL5 knockdown synergistically enhanced the attenuating effect of silencing CX3CL1 (fractalkine [FKN]) in adenovirus-induced acute liver injury. In addition, the combined treatment of human IL-10 expression with FKN knockdown would further strengthen the protective effect of silencing FKN. We used a hepatocyte-specific promoter to construct a hepatocyte-specific multiple function vector, which could simultaneously overexpress human IL-10 and knock down CCL5 and FKN expression. This vector could attenuate adenovirus-induced acute hepatitis highly efficiently by reducing liver NK cell recruitment and serum IFN-γ and TNF-α. The multiple function vectors could be delivered by nonviral (hydrodynamic injection) and viral (adenovirus) approaches, and maintained long-term function (more than 1 month in mice). Our results suggest a possible strategy to ameliorate the acute liver injury induced by adenovirus by modulating multiple immune genes. The novel multifunction vector has an extensive and practical use for polygenic and complex liver diseases such as malignancies and hepatitis, which correlate with multiple gene disorders.