Structure and regulation of cytoplasmic adapter proteins involved in innate immune signaling

Summary:  Initiation of the innate immune response requires agonist recognition by a pathogen recognition receptor. Following ligand binding, conformational rearrangement of the receptor creates a molecular scaffold from which signal transduction is propagated via complex cellular signaling pathways. This in turn leads to the induction of a pro-inflammatory immune response. A critical component of these signaling pathways is the homotypic interaction of receptor and adapter proteins via specific protein interaction domains. Within the innate immune signaling cascade, homotypic interactions between members of the death domain family and the Toll/interleukin-1 receptor domain are particularly important. Here we discuss the current understanding of the molecular basis of these homotypic receptor:adapter interactions and their role in innate immune signal transduction.     

A GTP-binding adapter protein couples TRAIL receptors to apoptosis-inducing proteins

Apoptosis-inducing tumor necrosis factor (TNF) family receptors recruit the proforms of caspase family cell death proteases to ligand-receptor complexes through interactions with intracellular adapter proteins. We have found that the GTP-binding protein DAP3 binds directly (with high affinity) to the death domain of TNF-related apoptosis-inducing ligand (TRAIL) receptors, and is required for TRAIL-induced apoptosis. DAP3 also associates with the pro-caspase-8--binding adapter protein Fas-associated death domain (FADD), and links FADD to the TRAIL receptors DR4 and DR5. We have also found that binding of DAP3 to FADD and activation of pro-caspase-8 in an in vitro reconstituted system is GTP-dependent. Elucidation of this mechanism suggests GTP-binding proteins as potential targets for pharmacological intervention in TRAIL-induced apoptosis.     

Semaphorins and their receptors in immune cell interactions

Semaphorins are newcomers to the growing panoply of immunoregulatory proteins. Members of this family were originally identified as proteins that provide axonal guidance cues during neuronal development. However, accumulating evidence indicates that several semaphorins, called 'immune semaphorins', are crucial to various phases of the immune response, from initiation to terminal inflammatory processes. Extensive studies of immune semaphorins have shown not only differences but also parallels in semaphorin functions among physiologically distinct systems, providing unexpected but meaningful insights into the biological activities of this protein family. Here we review the present knowledge of the function of semaphorins and their receptors in the immune system, including the most recent advances in this field.     

皮质抑素在免疫系统中的作用

皮质抑素（cortistatin,CST）是一种新的生长抑素家族神经内分泌多肽,广泛分布于中枢神经系统、内分泌器官及免疫系统中,能够与生长抑素受体、生长素受体及MrgX2受体结合,发挥调节神经内分泌功能、诱导免疫耐受及抑制炎症反应的作用。作为一种抗炎因子,CST可能在败血症、克罗恩病及类风湿关节炎的治疗中发挥作用。CST亦能够抑制血管内皮细胞增殖及迁移,提示CST在心血管疾病的发生和治疗中可能具有一定的意义。     

Estrogen receptors and their roles in the immune and respiratory systems

Estrogen is an important hormone for health in both genders. It is indispensable to glucose homeostasis, immune robustness, bone health, cardiovascular health, and neural functions. The main way that estrogen acts in the cells is through estrogen receptors (ERs). The presence of specific estrogen receptors is required for estrogen to have its characteristic ubiquitous action in almost all tissues. Estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) are the major isoforms of estrogen that are highly specific in humans and enable selective hormonal actions in different tissues. This article reviews some of the observed estrogen actions and effects in different tissues and cells through these specific receptors. This ubiquitous, almost ordinary hormone may reveal itself as a significant factor that helped us to better understand the complexity of the human immune system response against respiratory infections, including the COVID-19, and especially in the current state of this painful pandemic.     

Role of Fcgamma receptors in immune regulation and diseases]

The activation threshold of cells in the immune system is often tuned by cell surface molecules. The Fc receptors expressed on various hematopoietic cells constitute critical elements for activating or down-modulating immune responses and combines humoral and cell-mediated immunity. Thus, Fc receptors are the intelligent sensors of the immune status in the individual. However, impaired regulation by Fc receptors will lead to unresponsiveness or hyperreactivity to foreign as well as self antigens. Murine models for autoimmune disease indicate the indispensable roles of the inhibitory Fc receptor in the suppression of such disorders, whereas activating-type FcRs are crucial for the onset and exacerbation of the disease. The development of many autoimmune diseases in humans may be caused by impairment of the human Fc receptor regulatory system. This review is aimed at providing a current overview of the mechanism of Fc receptor-based immune regulation and the possible scenario of how immunological disorders might result from their dysfunction.     

NMDA receptors and their interacting proteins in the postsynaptic density

Glutamate receptors and their cytoplasmic interacting proteins are thought to play an important role in the process of excitatory synaptic transmission in the mammalian central nervous system. NMDA receptors are a subtype of ionotropic glutamate receptors and specifically interact with PDZ-domain containing proteins such as PSD-95. This interaction is important in the clustering of NMDA receptors on the postsynaptic membrane and the molecular complex containing NMDA receptors and PSD-95 is likely to be the core structure of the postsynaptic density. In the first part of this review, biological significance of the diversity of NMDA receptor subunits is discussed. In the second part, implications obtained from our recent analyses on the structural remodeling of the postsynaptic density are presented.     

Multisubunit receptors in the immune system and their association with the cytoskeleton: In search of functional significance

Various multisubunit receptors of the immune system share similarities in structure and induce closely related signal transduction pathways upon ligand binding. Examples include the T cell antigen receptor (TCR), the B cell antigen receptor (BCR), and the high-affinity receptor for immunoglobulin E (FcεRI). Although these receptors are devoid of intrinsic kinase activity, they can associate with a similar array of intracellular kinases, phosphatases and other signaling molecules. Furthermore, these receptor complexes all form an association with the cytoskeletal matrix. In this review, we compare the structural and functional characteristics of the TCR, BCR and FcεRI. We examine the role of the cytoskeleton in regulating receptor-mediated signal transduction, as analyzed in other well-characterized receptors, including the epidermal growth factor receptor and integrin receptors. On the basis of this evidence, we review the current data depicting a cytoskeletal association for multisubunit immune system receptors and explore the potential bearing of this interaction on signaling function.     

Role of neuropilin-2 in the immune system

Neuropilins (NRPs) are single transmembrane receptors with short cytoplasmic tails and are dependent on receptors like VEGF receptors or Plexins for signal transduction. NRPs are known to be important in angiogenesis, lymphangiogenesis, and axon guidance. The Neuropilin-family consists of two members, Neuropilin-1 (NRP1) and Neuropilin-2 (NRP2). They are up to 44 % homologous and conserved in all vertebrates. High levels of NRP2 are found on immune cells. Current research is very limited regarding the functions of NRP2 on these cells. Recent evidence suggests that NRP2 is important for migration, antigen presentation, phagocytosis and cell–cell contact within the immune system. Additionally, posttranslational NRP2 modifications like polysialylation are crucial for the function of some immune cells. This review is an overview about expression and functions of NRP2 in the immune system.     

ADAM family proteins in the immune system.

CD156 is a member of a family proteins characterized by a disintegrin and a metalloprotease domain (ADAM). These molecules are phylogenically conserved but have individual roles in a variety of cells. Here, Shunsuke Yamamoto and colleagues discuss data suggesting that ADAM family proteins have important roles in the immune system.     

趋化因子及其受体与特应性皮炎

趋化因子及其受体在许多疾病的病理生理过程中起着重要作用,是当前医学科研领域的一个热点。近年来趋化因子及其受体在特应性皮炎（AD）中的研究显示CC型趋化因子、CX3C型趋化因子、CXC型趋化因子及其受体与AD的发病机制、临床表现、SCORAD评分、病情活动、治疗反应、治疗监测等关系密切,这对探讨AD发病机制和探索新的治疗方案具有重要意义。     

Chemokine receptors and leukocyte trafficking in the mucosal immune system

The CC chemokine receptors CCR6, CCR9, and CCR10 all contribute to the positioning of leukocytes at mucosal locations. Mucosal epithelial cells are major sources of the chemokine ligands for each of these receptors, although the pattern of expression of the individual ligands differs at distinct mucosal sites. CCR6 is expressed by most B cells, subsets of CD4 and CD8 memory T cells, and subsets of dendritic cells (DCs). Absence of CCR6 in mice leads to abnormal expansion of intestinal intraepithelial T cells and lamina propria T cells, smaller Peyer's patches, and defects in IgA-mediated responses to oral antigens and pathogens. CCR9 is present on thymocytes, most intestinal intraepithelial lymphocytes, and other types of intestine-homing T cells. CCR 10 is found on skin-homing T cells and also direct IgA-producing plasma cells into mucosal sites. This review discusses the role of these chemokine receptors in homeostatic regulation of the mucosal immune system.     

The role of Toll-like receptors and related receptors of the innate immune system in asthma

PURPOSE OF REVIEW: The biology of the innate immunity receptors is of central importance in the host response to the environment. Identifying genetic variants that alter the innate immune response is highly relevant to understanding asthma pathogenesis. This review summarizes recent studies of the role of innate immunity receptors, including Toll-like receptors and CD14, in the pathogenesis of asthma. RECENT FINDINGS: The majority of studies published since 2004 have been genetic association studies in various clinical settings, which have found positive associations of single nucleotide polymorphisms in TLR2, TLR4, TLR6 and TLR10 with asthma or atopy, although the number of studies is small and the results not yet replicated. The designs for CD14 genetic studies have been more sophisticated and have included gene-environment interaction. The results of CD14 gene associations with asthma and atopy are suggestive but have not been fully replicated. Potential reasons for non-replication of TLR and CD14 association studies include insufficient power, type I error, population heterogeneity and different phenotypes studied. In addition, there may be differences in CD14 genetic effects between childhood and adulthood, and between levels of endotoxin exposure. SUMMARY: The evidence is still being accumulated for the role of Toll-like receptor polymorphisms in the pathogenesis of asthma. There is emerging evidence for the role of CD14 polymorphisms in the development of asthma and atopy. Further studies of innate immunity in asthma and allergy are required, using rigorous study design, measurement of environmental exposure and intermediate phenotypes to demonstrate single nucleotide polymorphism functionality.     

Histamine,histamine receptors and their role in immune pathology

The important roles of histamine in body physiology and various pathologic events have been well established, whereas new and exciting findings are still being uncovered. Histamine is not only the major mediator of the acute inflammatory and immediate hypersensitivity responses, but has also been demonstrated to affect chronic inflammation and regulate several essential events in the immune response. The diverse effects of histamine on immune regulation are due to the differential expression and regulation of four histamine receptors (HR) and their distinct intracellular signals. Differences in the affinities of these receptors are highly decisive on the biological effects of histamine and agents that target HRs. In particular, the discovery of reciprocal regulation of T cell activity by H1 and H2 receptor activation indicating histamine‐cytokine cross‐talk, as well as the characterization of the fourth histamine receptor (HR4) and its expression on numerous immune and inflammatory cells have prompted a re‐evaluation of the actions of histamine. This accounts for a new potential for HR antagonists and agonists in targeting various immunopathologic conditions.     

趋化因子及其受体在肿瘤血管生成中的作用及意义

趋化因子受体属于G蛋白偶联受体超家族,是含7个穿膜区段的单链受体,胞内区与G蛋白偶联,可产生信号转导。其在多种肿瘤细胞和肿瘤间质细胞膜上有功能性表达,趋化因子受体与肿瘤多种生物学行为密切相关。在肿瘤血管生成中,不同的趋化因子产生不同的生物学效应,提示可能存在不同的作用机制,成为新的抗癌策略靶点。     

趋化因子及其受体与气道疾病关系的研究进展

气道慢性炎症是哮喘和慢性阻塞性肺疾病的本质特点。炎症细胞浸润组织是炎症和宿主免疫应答的基础，这一过程受到趋化因子的控制。本文将阐述趋休因子及其受体家族的特点，特别是在慢性气道炎症病理生理过程中的作用以及作为气道慢性炎症靶向性治疗的可能性。