Intracellular double-stranded RNA (dsRNA) is a chief sign of replication for many viruses. Host mechanisms detect the dsRNA and initiate antiviral responses. In this report, we identify retinoic acid inducible gene I (RIG-I), which encodes a DExD/H box RNA helicase that contains a caspase recruitment domain, as an essential regulator for dsRNA-induced signaling, as assessed by functional screening and assays. A helicase domain with intact ATPase activity was responsible for the dsRNA-mediated signaling. The caspase recruitment domain transmitted 'downstream' signals, resulting in the activation of transcription factors NF-kappaB and IRF-3. Subsequent gene activation by these factors induced antiviral functions, including type I interferon production. Thus, RIG-I is key in the detection and subsequent eradication of the replicating viral genomes.

The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses.

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.

https://biblio.ugent.be/publication/8555786/file/8555788.pdf

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

■ Abstract Apoptosis is a genetically programmed, morphologically distinct form of cell death that can be triggered by a variety of physiological and pathological stimuli. Studies performed over the past 10 years have demonstrated that proteases play critical roles in initiation and execution of this process. The caspases, a family of cysteine-dependent aspartate-directed proteases, are prominent among the death proteases. Caspases are synthesized as relatively inactive zymogens that become activated by scaffold-mediated transactivation or by cleavage via upstream proteases in an intracellular cascade. Regulation of caspase activation and activity occurs at several different levels: ( a) Zymogen gene transcription is regulated; ( b) antiapoptotic members of the Bcl-2 family and other cellular polypeptides block proximity-induced activation of certain procaspases; and ( c) certain cellular inhibitor of apoptosis proteins (cIAPs) can bind to and inhibit active caspases. Once activated, caspases cleave a variety of intracellular polypeptides, including major structural elements of the cytoplasm and nucleus, components of the DNA repair machinery, and a number of protein kinases. Collectively, these scissions disrupt survival pathways and disassemble important architectural components of the cell, contributing to the stereotypic morphological and biochemical changes that characterize apoptotic cell death.

Mammalian caspases: structure ,a ctivation ,s ubstrates, and functions during apoptosis

In 2009, the Nomenclature Committee on Cell Death (NCCD) proposed a set of recommendations for the definition of distinct cell death morphologies and for the appropriate use of cell death-related terminology, including 'apoptosis', 'necrosis' and 'mitotic catastrophe'. In view of the substantial progress in the biochemical and genetic exploration of cell death, time has come to switch from morphological to molecular definitions of cell death modalities. Here we propose a functional classification of cell death subroutines that applies to both in vitro and in vivo settings and includes extrinsic apoptosis, caspase-dependent or -independent intrinsic apoptosis, regulated necrosis, autophagic cell death and mitotic catastrophe. Moreover, we discuss the utility of expressions indicating additional cell death modalities. On the basis of the new, revised NCCD classification, cell death subroutines are defined by a series of precise, measurable biochemical features.

/pdf/molecular-definitions-of-cell-death-subroutines-q5g428rlyi.pdf

Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012

Interleukin 6 (IL-6) has a broad effect on cells of the immune system and those not of the immune system and often displays hormone-like characteristics that affect homeostatic processes. IL-6 has context-dependent pro- and anti-inflammatory properties and is now regarded as a prominent target for clinical intervention. However, the signaling cassette that controls the activity of IL-6 is complicated, and distinct intervention strategies can inhibit this pathway. Clinical experience with antagonists of IL-6 has raised new questions about how and when to block this cytokine to improve disease outcome and patient wellbeing. Here we discuss the effect of IL-6 on innate and adaptive immunity and the possible advantages of various antagonists of IL-6 and consider how the immunobiology of IL-6 may inform clinical decisions.

/pdf/il-6-as-a-keystone-cytokine-in-health-and-disease-c7lxehv1qz.pdf

IL-6 as a keystone cytokine in health and disease

We report an incipient case of intranuclear inclusion body disease (INIBD) in a 78-year-old woman. No apparent neurological symptoms were noticed during the clinical course. Post mortem examination revealed widespread occurrence of eosinophilic intranuclear inclusions in neuronal and glial cells of the central and peripheral nervous systems, as well as in parenchymal cells of the visceral organs. The inclusions were observed more frequently in glial cells than in neuronal cells. Ultrastructurally, the inclusions consisted of granular and filamentous material. Immunohistochemically, the inclusions were positive for ubiquitin, ubiquitin-related proteins (NEDD8 ultimate buster 1, small ubiquitin modifier-1, small ubiquitin modifier-2 and p62), promyelocytic leukemia protein and abnormally expanded polyglutamine. Consistent with previous studies, the vast majority of inclusion-bearing glial cells were astrocytes. Furthermore, p25α-positive oligodendrocytes rarely contained intranuclear inclusions. These findings suggest that INIBD may occur in non-demented elderly individuals and that oligodendrocyte is also involved in the disease process of INIBD.

Incipient intranuclear inclusion body disease in a 78-year-old woman.

Platelet-activating factor enhances the expression of vascular endothelial growth factor in normal human astrocytes.

Cystatin C (CC), a cysteine protease inhibitor involved in protein degradation, is a marker of Bunina bodies in lower motor neurons in amyotrophic lateral sclerosis (ALS). TAR-DNA binding protein-43 (TDP-43)-immunoreactive inclusions are also histological hallmarks of ALS but whether CC is found in motor neurons with or without TDP-43-positive inclusions in ALS is not known. To determine whether inclusion body formation affects cytoplasmic CC immunoreactivity, we examined spinal cords from 9 ALS patients and 12 control subjects by immunohistochemistry. Most anterior horn cells (AHCs) showed moderate to intense immunoreactivity in controls, whereas CC immunoreactivity was markedly decreased in AHCs in ALS cases. The proportion of CC-immunolabeled AHCs was reduced regardless of whether they contained Bunina bodies. In contrast, the proportion of CC-immunolabeled AHCs was significantly reduced in those with TDP-43 inclusions. Cystatin C immunoreactivity of astrocytes in the spinal gray matter and white matter in ALS was significantly decreased compared with controls. These findings suggest that the formation of TDP-43 inclusions, but not of Bunina bodies, may be linked to the content of CC in spinal motor neurons and that perturbations in endogenous levels of CC in neuronal and glial cells may be part of the neurodegenerative processes in ALS.

Decreased Cystatin C Immunoreactivity in Spinal Motor Neurons and Astrocytes in Amyotrophic Lateral Sclerosis

Multiple system atrophy (MSA) is divided into two clinical subtypes: MSA with predominant parkinsonian features (MSA-P) and MSA with predominant cerebellar dysfunction (MSA-C). We report a 71-year-old Japanese man without clinical signs of MSA, in whom post mortem examination revealed only slight gliosis in the pontine base and widespread occurrence of glial cytoplasmic inclusions in the central nervous system, with the greatest abundance in the pontine base and cerebellar white matter. Neuronal cytoplasmic inclusions (NCIs) and neuronal nuclear inclusions (NNIs) were almost restricted to the pontine and inferior olivary nuclei. It was noteworthy that most NCIs were located in the perinuclear area, and the majority of NNIs were observed adjacent to the inner surface of the nuclear membrane. To our knowledge, only four autopsy cases of preclinical MSA have been reported previously, in which neuronal loss was almost entirely restricted to the substantia nigra and/or putamen. Therefore, the present autopsy case of preclinical MSA-C is considered to be the first of its kind to have been reported. The histopathological features observed in preclinical MSA may represent the early pattern of MSA pathology.

An autopsy case of preclinical multiple system atrophy (MSA-C)

It has been reported that the alizarin red S technique may be used to visualize both intracellular and extracellular calcium deposits. Using this method histologic observations of the nervous system were made in rats that were given dimethyl mercury at 5 mg/kg per day for 12 consecutive days, and killed on days 1, 4, 7, 10, 12, 24, 32, 49, 100 and 140 (day 0 was the day that the final dose was administered). Neuronal degeneration with calcium deposition was found in the nervous system from day 4 onward. In the cerebellum alizarin red S-positive granules became gradually larger with time after dimethyl mercury administration, and large calcospherites were observed from day 32 onward. In contrast, the visualization of calcium deposits in the cerebral cortex was restricted to days 10-12. Calcium deposits were found in the ascending axons of the dorsal root ganglion neurons (dorsal fascicles of the spinal cord), but not in their perikarya. These findings suggest that widespread calcium deposition could occur in the nervous system following dimethyl mercury exposure, and that in the rat the mechanism of calcium deposition differs depending upon the brain region.

Kunikazu Tanji

Papers

Incipient intranuclear inclusion body disease in a 78-year-old woman.

Platelet-activating factor enhances the expression of vascular endothelial growth factor in normal human astrocytes.

Decreased Cystatin C Immunoreactivity in Spinal Motor Neurons and Astrocytes in Amyotrophic Lateral Sclerosis

An autopsy case of preclinical multiple system atrophy (MSA-C)

Widespread calcium deposits, as detected using the alizarin red S technique, in the nervous system of rats treated with dimethyl mercury.