Hepatic stellate cells and innate immunity in alcoholic liver disease

Constant alcohol consumption is a major cause of chronic liver disease, and there has been a growing concern regarding the increased mortality rates worldwide. Alcoholic liver diseases (ALDs) range from mild to more severe conditions, such as steatosis, steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. The liver is enriched with innate immune cells (e.g. natural killer cells and Kupffer cells) and hepatic stellate cells (HSCs), and interestingly, emerging evidence suggests that innate immunity contributes to the development of ALDs (e.g. steatohepatitis and liver fibrosis). Indeed, HSCs play a crucial role in alcoholic steatosis via production of endocannabinoid and retinol metabolites. This review describes the roles of the innate immunity and HSCs in the pathogenesis of ALDs, and suggests therapeutic targets and strategies to assist in the reduction of ALD.

Hepatic non-parenchymal cells:Master regulators ofalcoholic liver disease?

Chronic alcohol consumption is one of the most common causes of the progression of alcoholic liver disease(ALD). In the past, alcohol-mediated hepatocyte injury was assumed to be a significantly major cause of ALD. However, a huge number of recent and brilliant studies have demonstrated that hepatic non-parenchymal cells including Kupffer cells, hepatic stellate cells, liver sinusoidal endothelial cells and diverse types of lymphocytes play crucial roles in the pathogenesis of ALD by producing inflammatory mediators such as cytokines, oxidative stress, micro RNA, and lipid-originated metabolites(retinoic acid and endocannabinoids) or by directly interacting with parenchymal cells(hepatocytes). Therefore, understanding the comprehensive roles of hepatic nonparenchymal cells during the development of ALD will provide new integrative directions for the treatment of ALD. This review will address the roles of nonparenchymal cells in alcoholic steatosis, inflammation, and liver fibrosis and might help us to discover possible therapeutic targets and treatments involving modulating the non-parenchymal cells in ALD.

3D cellular visualization of intact mouse tooth using optical clearing without decalcification

Dental pulp is composed of nerves,blood vessels,and various types of cells and surrounded by a thick and hard enamel-dentin matrix.Due to its importance in the maintenance of tooth vitality,there have been intensive efforts to analyze the complex cellularlevel organization of the dental pulp in teeth.Although conventional histologic analysis has provided microscopic images of the dental pulp,3-dimensional (3D) cellular-level visualization of the whole dental pulp in an intact tooth has remained a technically challenging task.This is mainly due to the inevitable disruption and loss of microscopic structural features during the process of mechanical sectioning required for the preparation of the tooth sample for histological observation.To accomplish 3D microscopic observation of thick intact tissue,various optical clearing techniques have been developed mostly for soft tissue,and their application for hard tissues such as bone and teeth has only recently started to be investigated.In this work,we established a simple and rapid optical clearing technique for intact mouse teeth without the time-consuming process of decalcification.We achieved 3D cellular-level visualization of the microvasculature and various immune cell distributions in the whole dental pulp of mouse teeth under normal and pathologic conditions.This technique could be used to enable diverse research methods on tooth development and regeneration by providing 3D visualization of various pulpal cells in intact mouse teeth.

New insights in the pathogenesis of alcohol-related liver disease:The metabolic,immunologic,and neurologic pathways

Alcohol-related liver disease(ALD)became an important health issue worldwide.Following chronic alcohol consumption,the development of ALD might be caused by metabolic and immunologic factors,such as reactive oxygen species(ROS)and pro-inflammatory cytokines.For example,hepatic cytochrome P4502E1 enzyme increases ROS production and stimulates de novo lipogenesis after alcohol exposure.In addition,damage-and pathogen-associated molecular patterns stimulate their specific receptors in nonparenchymal cells,including Kupffer cells,hepatic stellate cells(HSCs),and lymphocytes,which result in hepatocyte death and infiltration of pro-inflammatory cells(e.g.,neutrophils and macrophages)in the liver.Moreover,our studies have suggested the novel involvement of neurologic signaling pathways(e.g.,endocannabinoid and glutamate)through the metabolic synapse between hepatocytes and HSCs in the development of alcohol-related hepatic steatosis.Additionally,agouti-related protein and beta2-adrenergic receptors aggravate hepatic steatosis.Furthermore,organ-crosstalk has emerged as a critical issue in ALD.Chronic alcohol consumption induces dysbiosis and barrier disruption in the gut,leading to endotoxin leakage into the portal circulation,or lipolysis-mediated transport of triglycerides from the adipose tissue to the liver.In summary,this review addresses multiple pathogeneses of ALD,provides novel neurologic signaling pathways,and emphasizes the importance of organ-crosstalk in the development of ALD.

Regulation of c-SMAC formation and AKT-mTOR signaling by the TSG101-IFT20 axis in CD4^(+)T cells

CD4^(+)T cells play major roles in the adaptive immune system,which requires antigen recognition,costimulation,and cytokines for its elaborate orchestration.Recent studies have provided new insight into the importance of the supramolecular activation cluster(SMAC),which comprises concentric circles and is involved in the amplification of CD4^(+)T cell activation.However,the underlying mechanism of SMAC formation remains poorly understood.Here,we performed single-cell RNA sequencing of CD4^(+)T cells left unstimulated and stimulated with anti-CD3 and anti-CD28 antibodies to identify novel proteins involved in their regulation.We found that intraflagellar transport 20(IFT20),previously known as cilia-forming protein,was upregulated in antibody-stimulated CD4^(+)T cells compared to unstimulated CD4^(+)T cells.We also found that IFT20 interacted with tumor susceptibility gene 101(TSG101),a protein that endocytoses ubiquitinated T-cell receptors.The interaction between IFT20 and TSG101 promoted SMAC formation,which led to amplification of AKT-mTOR signaling.However,IFT20-deficient CD4^(+)T cells showed SMAC malformation,resulting in reduced CD4^(+)T cell proliferation,aerobic glycolysis,and cellular respiration.Finally,mice with T-cell-specific IFT20 deficiency exhibited reduced allergen-induced airway inflammation.Thus,our data suggest that the IFT20-TSG101 axis regulates AKT-mTOR signaling via SMAC formation.

PD-1 blockade-unresponsive human tumor-infiltrating CD8^(+)T cells are marked by loss of CD28 expression and rescued by IL-15

Blockade of programmed death-1(PD-1)reinvigorates exhausted CD8^(+)T cells,resulting in tumor regression in cancer patients.Recently,reinvigoration of exhausted CD8^(+)T cells following PD-1 blockade was shown to be CD28-dependent in mouse models.Herein,we examined the role of CD28 in anti-PD-1 antibody-induced human T cell reinvigoration using tumor-infiltrating CD8^(+)T cells(CD8^(+)TILs)obtained from non-small-cell lung cancer patients.Single-cell analysis demonstrated a distinct expression pattern of CD28 between mouse and human CD8^(+)TILs.Furthermore,we found that human CD28^(+)CD8^(+)but not CD28^(–)CD8^(+)TILs responded to PD-1 blockade irrespective of B7/CD28 blockade,indicating that CD28 costimulation in human CD8^(+)TILs is dispensable for PD-1 blockade-induced reinvigoration and that loss of CD28 expression serves as a marker of anti-PD-1 antibody-unresponsive CD8^(+)TILs.Transcriptionally and phenotypically,PD-1 blockade-unresponsive human CD28^(–)PD-1^(+)CD8^(+)TILs exhibited characteristics of terminally exhausted CD8^(+)T cells with low TCF1 expression.Notably,CD28^(–)PD-1^(+)CD8^(+)TILs had preserved machinery to respond to IL-15,and IL-15 treatment enhanced the proliferation of CD28^(–)PD-1^(+)CD8^(+)TILs as well as CD28^(+)PD-1^(+)CD8^(+)TILs.Taken together,these results show that loss of CD28 expression is a marker of PD-1 blockade-unresponsive human CD8^(+)TILs with a TCF1–signature and provide mechanistic insights into combining IL-15 with anti-PD-1 antibodies.

Attractor landscape analysis of the cardiac signaling network reveals mechanism-based therapeutic strategies for heart failure

cardiomyocytes 的 Apoptosis 和肥大是心失败(HF ) 的主要原因，死亡的一个全球带原因，并且通过复杂细胞内部的发信号网络被调整，由于它的复杂性限制有效处理的开发。为了在一个系统为 HF 识别有效治疗学的策略，铺平，我们由集成所有可得到的试验性的证据开发心脏的发信号网络的一个大规模全面数学模型。网络模型的引起注意的人风景分析识别有效地在 ischemic 下面压制 cardiomyocytes 的 apoptosis 和肥大或迫使导致超载的 HF 的控制节点的不同集合， HF 的二种主要类型。有趣地，我们的系统级的分析建议这些控制节点的干预可以为 HF 增加临床的药的功效并且，大多数重要性，控制节点的不同联合作为取决于 HF 的类型的潜在地有效的候选人药目标被建议。我们的学习提供为 HF 开发基于机制的治疗学的策略的一个系统的方法。

Landscapes of SARS-CoV-2-reactive CD8^(+)T cells:heterogeneity of host immune responses against SARS-CoV-2

In a recent study published in Science Immunology,^Kusnadi et al.performed single-cell RNA sequencing(scRNA-seq)of SARS-CoV-2-reactive CD8^(+)T cells and reported heterogeneity.SARS-CoV-2 infection causes COVID-19,which is an ongoing pandemic disease threatening public health.The virology of SARS-CoV-2 and immune responses against the virus have been urgently investigated to develop effective measures against COVID-19.During viral infection,CD84 T cells contribute to elimination of the virus by exerting cytotoxicity against virus-infected cells and producing effector cytokines,whereas neutralizing antibodies interfere with viral entry of host cells.

SARS-CoV-2 mutations, vaccines, and immunity: implication of variants of concern

In a recent study published in Nature,Wang et al.1 investigated the neutralizing activities of antibodies elicited by COVID-19 mRNA vaccines and natural infection with SARS-CoV-2 against SARS-CoV-2 variants.The devastating impact of the ongoing COVID-19 pandemic on public health,the economy,and society has made vaccine development a top priority for global health.Thus,vaccine development is progressing at an unprecedented pace as an urgent response to COVID-19.

Increased type III interferons and NK cell functions in SARS-CoV-2-infected children

Dear Editor,Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection is more likely to progress to severe disease in the elderly,and the rates of hospitalization for coronavirus disease 2019(COVID-19)increase with age.1,2 Herein,we comprehensively compared adaptive and innate immune responses between children and adults infected with SARS-CoV-2.

β-Arrestin 2 suppresses the activation of YAP by promoting LATS kinase activity

Dysregulation of the Hippo pathway has been frequently identified in various human cancers. The Hippo pathway is a highly complex pathway involving multiple types of proteins, and the activation of YAP by LATS kinase is the final effector step in the transcription process. In this study, we linked the roles of the multifunctional adapter proteins β-arrestins (β-arrestin 1 and 2) in cooperation with other signaling pathways such as GPCR and Wnt to essential cellular functions involved in carcinogenesis, including the regulation of cell proliferation, migration, and differentiation as well as stem cell properties.1 Although β-arrestin 1 and 2 have high structural similarities, they have different roles in carcinogenesis as β-arrestin 1 aids cancer cell survival and metastasis2 and β-arrestin 2 inhibits tumor growth.1 In the Hippo signaling pathway, β-arrestins function as scaffold proteins that mediate the phosphorylation of key molecules, and their association with human cancers is a major research topic. In this study, we demonstrated that β-arrestin 2 inhibits YAP activation through the formation of the β-arrestin 2-LATS-YAP trimeric complex, which results in the promotion of the kinase activity of LATS in cancer cell lines and patient-derived colon cancer organoids.

Activation or exhaustion of CD8^(+) T cells in patients with COVID-19

In addition to CD4^(+)T cells and neutralizing antibodies,CD8^(+)T cells contribute to protective immune responses against SARS-CoV-2 in patients with coronavirus disease 2019(COVID-19),an ongoing pandemic disease.In patients with COVID-19,CD8^(+)T cells exhibiting activated phenotypes are commonly observed,although the absolute number of CD8^(+)T cells is decreased.In addition,several studies have reported an upregulation of inhibitory immune checkpoint receptors,such as PD-1,and the expression of exhaustion-associated gene signatures in CD8^(+)T cells from patients with COVID-19.However,whether CD8^(+)T cells are truly exhausted during COVID-19 has been a controversial issue.In the present review,we summarize the current understanding of CD8^(+)T-cell exhaustion and describe the available knowledge on the phenotypes and functions of CD8^(+)T cells in the context of activation and exhaustion.We also summarize recent reports regarding phenotypical and functional analyses of SARS-CoV-2-specific CD8^(+)T cells and discuss long-term SARS-CoV-2-specific CD8^(+)T-cell memory.

Harnessing novel engineered feeder cells expressing activating molecules for optimal expansion of NK cells with potent antitumor activity

Natural killer(NK)cells play an important role in the antitumor immune response as the major cytotoxic lymphocytes in the innate immune system.NK cells without any genetic modifications have been used for both autologous and allogeneic therapies.Moreover,many reports have suggested that allogeneic NK cells can reduce the recurrence of disease and improve survival through a graft-versus-leukemia effect without GVHD[1,2].

Functions of hepatic non-parenchymal cells in alcoholic liver disease

Alcoholic liver disease(ALD)represents a wide spectrum of disease from simple steatosis to cirrhosis.Although there have been multiple attempts to treat ALD,its treatment is still based on abstinence from alcohol and using corticosteroids in specified cases.However,nearly 40%of patients with ALD who are in need of treatment are unresponsive to the current treatments,which implies a new paradigm shift for the treatment of ALD.Traditionally,earlier studies have focused on the abnormal metabolism occurring in the hepatocytes as a protagonist in the pathogenesis of ALD.However,increasing evidence suggests that non-parenchymal cells,such as hepatic stellate cells(HSCs),Kupffer cells,liver sinusoidal endothelial cells,and immune cells around the hepatocytes have critical roles in multiple stages of ALD either by direct or indirect cell-to-cell interactions.For instance,in the early stage of ALD,Kupffer cells and HSCs located closely to hepatocytes contribute to the development of alcoholic steatosis and inflammation through the secretion of various inflammatory cytokines(immunologic pathways)and the activation of the endocannabinoid system(metabolic pathways).While the stage of ALD progresses to alcoholic hepatitis and fibrosis,various cell-to-cell interactions with infiltrating immune cells become highly significant at the multicellular level.This review explains the diverse roles of non-parenchymal cells in the progression of ALD,as well as potential therapeutic strategies to treat ALD.

Aged T cells and cardiovascular disease

Memory T cells undergo replicative senescence via repetitive proliferation.As in other cells,replicative senescence of T cells is characterized by shortened telomeres.1 Immunophenotypes are also altered in replicative senescent T cells compared to young T cells.In humans,replicative senescent T cells typically lose expression of CD28,a costimulatory receptor,and acquire the expression of CD57 antigen,a terminally sulfated glycan carbohydrateepitope,1 though the mechanism underlying this regulation has not yet been clearly elucidated.Therefore,CD28−or CD57+T cells are considered replicative senescent T cells in humans.

T cell epitopes in SARS-CoV-2 proteins are substantially conserved in the Omicron variant

In November 2021,the Omicron variant(B.1.1.529)emerged and was designated a variant of concern(VOC)by the World Health Organization.Recently,Omicron was reported to extensively escape neutralizing antibodies elicited by COVID-19 vaccination or natural infection[1,2,3].However,whether Omicron evades the T cell immunity elicited by COVID-19 vaccination or natural infection remains to be elucidated.To address this issue,we analyzed the amino acid sequences of T cell epitopes identified from the original SARS-CoV-2 strain(Wuhan-Hu-1)in the Omicron variant(hCoV-19/South Africa/CERI-KRISP-K032284/2021).