The alliance of sphingosine-1-phosphate and its receptors in immunity

Sphingosine-1-phosphate (S1P) is a biologically active metabolite of plasma-membrane sphingolipids that is essential for immune-cell trafficking. Its concentration is increased in many inflammatory conditions, such as asthma and autoimmunity. Much of the immune function of S1P results from the engagement of a family of G-protein-coupled receptors (S1PR1-S1PR5). Recent findings on the role of S1P in immunosurveillance, the discovery of regulatory mechanisms in S1P-mediated immune-cell trafficking and new advances in understanding the mechanism by which S1P affects immune-cell function indicate that the alliance between S1P and its receptors has a fundamental role in immunity.     

Controlled One-on-One Encounters between Immune Cells and Microbes Reveal Mechanisms of Phagocytosis

Among many challenges facing the battle against infectious disease, one quandary stands out. On the one hand, it is often unclear how well animal models and cell lines mimic human immune behavior. On the other hand, many core methods of cell and molecular biology cannot be applied to human subjects. For example, the profound susceptibility of neutropenic patients to infection marks neutrophils (the most abundant white blood cells in humans) as vital immune defenders. Yet because these cells cannot be cultured or genetically manipulated, there are gaps in our understanding of the behavior of human neutrophils. Here, we discuss an alternative, interdisciplinary strategy to dissect fundamental mechanisms of immune-cell interactions with bacteria and fungi. We show how biophysical analyses of single-live-cell/single-target encounters are revealing universal principles of immune-cell phagocytosis, while also dispelling misconceptions about the minimum required mechanistic determinants of this process.     

Line tension and stability of domains in cell-adhesion zones mediated by long and short receptor-ligand complexes

Submicron scale domains of membrane-anchored receptors play an important role in cell signaling. Central questions concern the stability of these microdomains, and the mechanisms leading to the domain formation. In immune-cell adhesion zones, microdomains of short receptor-ligand complexes form next to domains of significantly longer receptor-ligand complexes. The length mismatch between the receptor-ligand complexes leads to membrane deformations and has been suggested as a possible cause of the domain formation. The domain formation is a nucleation and growth process that depends on the line tension and free energy of the domains. Using a combination of analytical calculations and Monte Carlo simulations, we derive here general expressions for the line tension between domains of long and short receptor-ligand complexes and for the adhesion free energy of the domains. We argue that the length mismatch of receptor-ligand complexes alone is sufficient to drive the domain formation, and obtain submicron-scale minimum sizes for stable domains that are consistent with the domain sizes observed during immune-cell adhesion.     

Die for the community: an overview of programmed cell death in bacteria

Programmed cell death is a process known to have a crucial role in many aspects of eukaryotes physiology and is clearly essential to their life. As a consequence, the underlying molecular mechanisms have been extensively studied in eukaryotes and we now know that different signalling pathways leading to functionally and morphologically different forms of death exist in these organisms. Similarly, mono-cellular organism can activate signalling pathways leading to death of a number of cells within a colony. The reason why a single-cell organism would activate a program leading to its death is apparently counterintuitive and probably for this reason cell death in prokaryotes has received a lot less attention in the past years. However, as summarized in this review there are many reasons leading to prokaryotic cell death, for the benefit of the colony. Indeed, single-celled organism can greatly benefit from multicellular organization. Within this forms of organization, regulation of death becomes an important issue, contributing to important processes such as: stress response, development, genetic transformation, and biofilm formation.     

Hyperphagia by self- and xeno-cannibalism: cell death by indigestion?: a reminiscence of the Phedrus Fabula "Rana Rupta et Bos"?

The occurrence of self- and xeno-cannibalism could be considered as two different aspects of the same well-regulated process. The formation of autophagosomes can represent a survival option for a cell in unfavorable conditions but it can also lead to cell demise. In fact, autophagy has been considered as an additional and clear-cut cell death pathway. We herein speculate that selfeating by autophagy could be paralleled by a cannibalistic behavior, e.g., by cell feeding of siblings, that can also become detrimental. This behavior in fact, once exacerbated, can also lead to cell death, probably bolstering intracellular oxidative imbalance. In this case, a survival option, such as self- and xeno-cannibalism, can be turned into a peculiar death option: cell death by feeding excess. Under this point of view, over-feeding cells are reminiscent of the frog in the Phedrus Fabula "Rana Rupta et Bos".     

Ion channels and apoptosis in cancer

Humans maintain a constant cell number throughout their lifespan. This equilibrium of cell number is accomplished when cell proliferation and cell death are kept balanced, achieving a steady-state cell number. Abnormalities in cell growth or cell death can lead to an overabundance of cells known as neoplasm or tumours. While the perception of cancer is often that of an uncontrollable rate of cell growth or increased proliferation, a decrease in cell death can also lead to tumour formation. Most cells when detached from their normal tissue die. However, cancer cells evade cell death, tipping the balance to an overabundance of cell number. Therefore, overcoming this resistance to cell death is a decisive factor in the treatment of cancer. Ion channels play a critical role in cancer in regards to cell proliferation, malignant angiogenesis, migration and metastasis. Additionally, ion channels are also known to be critical components of apoptosis. In this review, we discuss the modes of cell death focusing on the ability of cancer cells to evade apoptosis. Specifically, we focus on the role ion channels play in controlling and regulating life/death decisions and how they can be used to overcome resistance to apoptosis in the treatment of cancer.     

Identification of metabolism-associated molecular subtype in ovarian cancer

Ovarian cancer (OC) is the most lethal gynaecological cancer with genomic complexity and extensive heterogeneity. This study aimed to characterize the molecular features of OC based on the gene expression profile of 2752 previously characterized metabolism-relevant genes and provide new strategies to improve the clinical status of patients with OC. Finally, three molecular subtypes (C1, C2 and C3) were identified. The C2 subtype displayed the worst prognosis, upregulated immune-cell infiltration status and expression level of immune checkpoint genes, lower burden of copy number gains and losses and suboptimal response to targeted drug bevacizumab. The C1 subtype showed downregulated immune-cell infiltration status and expression level of immune checkpoint genes, the lowest incidence of BRCA mutation and optimal response to targeted drug bevacizumab. The C3 subtype had an intermediate immune status, the highest incidence of BRCA mutation and a secondary optimal response to bevacizumab. Gene signatures of C1 and C2 subtypes with an opposite expression level were mainly enriched in proteolysis and immune-related biological process. The C3 subtype was mainly enriched in the T cell-related biological process. The prognostic and immune status of subtypes were validated in the Gene Expression Omnibus (GEO) dataset, which was predicted with a 45-gene classifier. These findings might improve the understanding of the diversity and therapeutic strategies for OC.     

Hyperphagia by self- and xeno-cannibalism: Cell death by indigestion? A reminiscence of the Phedrus Fabula “Rana Rupta et Bos”?

The occurrence of self- and xeno-cannibalism could be considered as two different aspects of the same well-regulated process. The formation of autophagosomes can represent a survival option for a cell in unfavorable conditions but it can also lead to cell demise. In fact, autophagy has been considered as an additional and clear-cut cell death pathway. We herein speculate that self-eating by autophagy could be paralleled by a cannibalistic behavior, e.g., by cell feeding of siblings, that can also become detrimental. This behavior in fact, once exacerbated, can also lead to cell death, probably bolstering intracellular oxidative imbalance. In this case, a survival option, such as self- and xeno-cannibalism, can be turned into a peculiar death option: cell death by feeding excess. Under this point of view, over-feeding cells are reminiscent of the frog in the Phedrus Fabula “Rana Rupta et Bos”.     

The early lethality of autosomal monosomy in the mouse

Using male mice doubly heterozygous for pairs of Robertsonian translocation chromosomes that have one arm in common, mouse embryos monosomic for 11 of the 19 autosomes have been generated. All of these monosomies result in death prior to or during the implantation period, with only rare survivors being detected 6 days after fertilization. For some of the monosomies the onset of lethality can be detected during the third or fourth day of development, but others do not begin to die until sometime after the late blastocyst stage on day 4. Retardation of development, as revealed by decreased cell numbers, is often detectable prior to or after the onset of the lethal period. The period during which death occurs may spread over several days and does not coincide with any of the developmental landmarks of the pre- or peri-implantation period. Genetic factors that may affect the rate of cellular proliferation or other aspects of embryonic development appear to play an important role in determining exactly when individual monosomies result in death. The universal early lethality of the autosomal monosomies leads to the conclusion that a large number of loci scattered over all of the autosomes are involved in processes that are so concentration dependent that a 50% reduction is sufficient to produce very serious consequences.     

Ubiquitinated inclusions and neuronal cell death

Ubiquitinated inclusions and selective neuronal cell death are considered the pathological hallmarks of Parkinson's disease and other neurodegenerative diseases. Recent genetic, pathological and biochemical evidence suggests that dysfunction of ubiquitin-dependent protein degradation by the proteasome might be a contributing, if not initiating factor in the pathogenesis of these diseases. In neuronal cell culture models inhibition of the proteasome leads to cell death and formation of fibrillar ubiquitin and alpha-synuclein-positive inclusions, thus modeling some aspects of Lewy body diseases. The processes of inclusion formation and neuronal cell death share some common mechanisms, but can also be dissociated at a certain level.     

The SIRP family of receptors and immune regulation

The immune system must be highly regulated to obtain optimal immune responses for the elimination of pathogens without causing undue side effects. This tight regulation involves complex interactions between membrane proteins on leukocytes. Members of the signal-regulatory protein (SIRP) family, which are expressed mainly by myeloid cells, provide one example of these regulatory membrane proteins. There are three SIRP-family genes that encode proteins that have similar extracellular regions but different signalling potentials, and are therefore known as 'paired receptors'. In this Review, we describe recent studies defining the ligands of the SIRP-family members, with particular emphasis on relating the molecular interactions of these proteins to their role in immune-cell regulation.     

A primatological perspective on death

Some questions that arise from observations of responses to dead and dying individuals by nonhuman primates are discussed, focusing on psychological issues. The phenomenon of transport and care of dead infants is reviewed, along with the consequences of the mother dying for orphaned offspring. It is argued that particular attention should be paid to how the context of a death affects individuals, for example, traumatic accidental or predation-induced death versus peaceful death following illness. Some primates kill others of their own or other species, which raises additional questions about death awareness and empathy. Observations from both the field and captivity can contribute toward a better understanding of the psychological meaning of death for primates. Some aspects of death awareness recognized by developmental psychologists might help guide research efforts in this area.     

Mitochondria: Biological roles in platelet physiology and pathology

Mitochondria are key regulators of cellular energy and redox metabolism, also playing a central role in cell signaling and death pathways. A number of processes occur within mitochondria, including redox-dependent ATP synthesis by oxidative phosphorylation and reactive oxygen species production. Mitochondrial permeability transition is a reversible process that may lead to cell death and is regulated by calcium and reactive oxygen species. Functional mitochondria are present in platelets, and evidence has demonstrated the direct involvement of these organelles in cellular ATP production, redox balance, as well as in platelet activation and apoptosis. Here, we review aspects of platelet physiology in which mitochondria are involved, as well as assess their function as new tools for studying a number of human diseases.     

Immunoregulatory functions of surfactant proteins

Because the lungs function as the body's gas-exchange organ, they are inevitably exposed to air that is contaminated with pathogens, allergens and pollutants. Host-defence mechanisms within the lungs must facilitate clearance of inhaled pathogens and particles while minimizing an inflammatory response that could damage the thin, delicate gas-exchanging epithelium. Pulmonary surfactant is a complex of lipids and proteins that enhances pathogen clearance and regulates adaptive and innate immune-cell functions. In this article, I review the structure and functions of the surfactant proteins SP-A and SP-D in regulating host immune defence and in modulating inflammatory responses.     

Oral Administration of p-Hydroxycinnamic Acid Attenuates Atopic Dermatitis by Downregulating Th1 and Th2 Cytokine Production and Keratinocyte Activation

Atopic dermatitis (AD) is a complex disease that is caused by various factors, including environmental change, genetic defects, and immune imbalance. We previously showed that p-hydroxycinnamic acid (HCA) isolated from the roots of Curcuma longa inhibits T-cell activation without inducing cell death. Here, we demonstrated that oral administration of HCA in a mouse model of ear AD attenuates the following local and systemic AD manifestations: ear thickening, immune-cell infiltration, production of AD-promoting immunoregulatory cytokines in ear tissues, increased spleen and draining lymph node size and weight, increased pro-inflammatory cytokine production by draining lymph nodes, and elevated serum immunoglobulin production. HCA treatment of CD4⁺ T cells in vitro suppressed their proliferation and differentiation into Th1 or Th2 and their Th1 and Th2 cytokine production. HCA treatment of keratinocytes lowered their production of the pro-inflammatory cytokines that drive either Th1 or Th2 responses in AD. Thus, HCA may be of therapeutic potential for AD as it acts by suppressing keratinocyte activation and downregulating T-cell differentiation and cytokine production.     

Orchestrating brain-cell renewal: the role of immune cells in adult neurogenesis in health and disease

Immune cells and immune molecules have recently been shown to support neurogenesis from neural stem and progenitor cells in the adult brain. This non-classical immune activity takes place constantly under normal physiological conditions and is extended under acute pathological conditions to include the attraction of progenitor cells and induction of neurogenesis in regions of the adult central nervous system (CNS) in which formation of new neurons does not normally occur. We suggest that the immune system should be viewed as a novel player in the adult neural stem cell niche and a coordinator of cell renewal processes after injury. We discuss these notions in light of the well-known facts that both immune-cell activity and cell renewal are inherently limited in the adult CNS and that immune and stem cells provide the body's mechanisms of repair.     

Cell death and diseases related to oxidative stress:4-hydroxynonenal (HNE) in the balance

During the last three decades, 4-hydroxy-2-nonenal (HNE), a major α,β-unsaturated aldehyde product of n-6 fatty acid oxidation, has been shown to be involved in a great number of pathologies such as metabolic diseases, neurodegenerative diseases and cancers. These multiple pathologies can be explained by the fact that HNE is a potent modulator of numerous cell processes such as oxidative stress signaling, cell proliferation, transformation or cell death. The main objective of this review is to focus on the different aspects of HNE-induced cell death, with a particular emphasis on apoptosis. HNE is a special apoptotic inducer because of its abilities to form protein adducts and to propagate oxidative stress. It can stimulate intrinsic and extrinsic apoptotic pathways and interact with typical actors such as tumor protein 53, JNK, Fas or mitochondrial regulators. At the same time, due to its oxidant status, it can also induce some cellular defense mechanisms against oxidative stress, thus being involved in its own detoxification. These processes in turn limit the apoptotic potential of HNE. These dualities can imbalance cell fate, either toward cell death or toward survival, depending on the cell type, the metabolic state and the ability to detoxify.     

The debate about death: an imperishable discussion?

In this concise review we discuss some of the complex edges of the concept of death that arose after the notorious advances in science and medicine over the last 50 years, in which the classical cardio-pulmonary criteria have led to the neurological criteria of death. New complicated questions like the definition of death and the operational criteria for diagnosing it have arisen and we think that they are far from being adequately and satisfactorily solved. A number of important issues--like the reliability and differences between cardio-pulmonary versus brain based criteria of death, if death is an event or a process, the meaning of integration and irreversibility--have not yet received sufficient attention. Here we have approached the death problem from two (biological) complex system perspectives: the organism level and the cellular-molecular level. We also discuss issues from a third systemic approach, that is, the entire society, thus involving legal, religious, bioethical and political aspects of death. Our aim is to integrate new perspectives in order to promote further discussion on these critical yet frequently neglected issues.