Evaluation of the safety, tolerability, pharmacokinetics and pharmacodynamics of SM17 in healthy volunteers: results from pre-clinical models and a first-in-human, randomized, double blinded clinical trial.

Background: Alarmins mediate type 2 T helper cell (Th2) inflammation and serve as upstream signaling elements in allergic inflammation and autoimmune responses. The alarmin interleukin (IL)-25 binds to a multi-domain receptor consisting of IL-17RA and IL-17RB subunits, resulting in the release of Th2 cytokines IL-4, IL-5, IL-9 and IL-13 to drive an inflammatory response. Therefore, the blockage of IL-17RB via SM17, a novel humanized monoclonal antibody, offers an attractive therapeutic target for Th2-mediated diseases, such as asthma.

Suppression of NK Cell Activation by JAK3 Inhibition: Implication in the Treatment of Autoimmune Diseases.

Natural killer (NK) cell is an essential cytotoxic lymphocyte in our innate immunity. Activation of NK cells is of paramount importance in defending against pathogens, suppressing autoantibody production and regulating other immune cells. Common gamma chain (c) cytokines, including IL-2, IL-15, and IL-21, are defined as essential regulators for NK cell homeostasis and development.

Interleukins 4 and 21 Protect Anti-IgM Induced Cell Death in Ramos B Cells: Implication for Autoimmune Diseases.

Interleukins 4 (IL-4) and 21 (IL-21) belong to the common gamma chain cytokine family which are highly involved in the progression of autoimmune diseases. While IL-4 is well known to be involved in the suppression of apoptosis of autoreactive B cells, the role played by IL-21 remains unclear. In the current study, we activated the human Burkitt's lymphoma Ramos B cells with anti-IgM to mimic B cell hyperactivation observed in patients of autoimmune diseases.

Microglial-glucocorticoid receptor depletion alters the response of hippocampal microglia and neurons in a chronic unpredictable mild stress paradigm in female mice.

Chronic psychological stress is one of the most important triggers and environmental risk factors for neuropsychiatric disorders. Chronic stress can influence all organs via the secretion of stress hormones, including glucocorticoids by the adrenal glands, which coordinate the stress response across the body. In the brain, glucocorticoid receptors (GR) are expressed by various cell types including microglia, which are its resident immune cells regulating stress-induced inflammatory processes.

Sex Differences of Microglia and Synapses in the Hippocampal Dentate Gyrus of Adult Mouse Offspring Exposed to Maternal Immune Activation.

Schizophrenia is a psychiatric disorder affecting ∼1% of humans worldwide. It is earlier and more frequently diagnosed in men than woman, and men display more pronounced negative symptoms together with greater gray matter reductions. Our previous findings utilizing a maternal immune activation (mIA) mouse model of schizophrenia revealed exacerbated anxiety-like behavior and sensorimotor gating deficits in adult male offspring that were associated with increased microglial reactivity and inflammation in the hippocampal dentate gyrus (DG).

Alterations in Intrinsic and Synaptic Properties of Hippocampal CA1 VIP Interneurons During Aging.

Learning and memory deficits are hallmarks of the aging brain, with cortical neuronal circuits representing the main target in cognitive deterioration. While GABAergic inhibitory and disinhibitory circuits are critical in supporting cognitive processes, their roles in age-related cognitive decline remain largely unknown. Here, we examined the morphological and physiological properties of the hippocampal CA1 vasoactive intestinal peptide/calretinin-expressing (VIP+/CR+) type 3 interneuron-specific (I-S3) cells across mouse lifespan.

Microglial Ultrastructure in the Hippocampus of a Lipopolysaccharide-Induced Sickness Mouse Model.

Sickness behavior is a set of behavioral changes induced by infections and mediated by pro-inflammatory cytokines. It is characterized by fatigue, decreased appetite and weight loss, changes in sleep patterns, cognitive functions, and lost interest in social activity. It can expedite recovery by conserving energy to mount an immune response involving innate immunity.

Microglia in the developing prefrontal cortex of rats show dynamic changes following neonatal disconnection of the ventral hippocampus.

Impaired ventral hippocampal (VH)-prefrontal cortex (PFC) connectivity is implicated in many cognitive and behavioral disorders. Excitotoxic neonatal VH (nVH) lesion in rat pups has been shown to induce synaptic pruning in the PFC as well as behavioral changes of relevance to developmental neuropsychiatric disorders. In the current study, we hypothesized that microglia, immune cells required for proper brain development and plasticity, may play a role in the development of abnormal behaviors in the nVH-lesioned animals.

Ibuprofen prevents progression of ataxia telangiectasia symptoms in ATM-deficient mice.

Background: Inflammation plays a critical role in accelerating the progression of neurodegenerative diseases, such as Alzheimer's disease (AD) and ataxia telangiectasia (A-T). In A-T mouse models, LPS-induced neuroinflammation advances the degenerative changes found in cerebellar Purkinje neurons both in vivo and in vitro. In the current study, we ask whether ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), can have the opposite effect and delay the symptoms of the disease.

Nonfunctional mutant Wrn protein leads to neurological deficits, neuronal stress, microglial alteration, and immune imbalance in a mouse model of Werner syndrome.

Werner syndrome (WS) is a premature aging disorder caused by mutations in a RecQ-family DNA helicase, WRN. Mice lacking part of the helicase domain of the WRN orthologue exhibit many phenotypic features of WS, including metabolic abnormalities and a shorter lifespan. Yet, little is known about the impact of WRN mutations on the central nervous system in both humans and mouse models of WS.

ProMoIJ: A new tool for automatic three-dimensional analysis of microglial process motility.

Microglia, the immune cells of the central nervous system, continuously survey the brain to detect alterations and maintain tissue homeostasis. The motility of microglial processes is indicative of their surveying capacity in normal and pathological conditions. The gold standard technique to study motility involves the use of two-photon microscopy to obtain time-lapse images from brain slices or the cortex of living animals.

Microglia under psychosocial stressors along the aging trajectory: Consequences on neuronal circuits, behavior, and brain diseases.

Mounting evidence indicates the importance of microglia for proper brain development and function, as well as in complex stress-related neuropsychiatric disorders and cognitive decline along the aging trajectory. Considering that microglia are resident immune cells of the brain, a homeostatic maintenance of their effector functions that impact neuronal circuitry, such as phagocytosis and secretion of inflammatory factors, is critical to prevent the onset and progression of these pathological conditions. However, the molecular mechanisms by which microglial functions can be properly regulated under healthy and pathological conditions are still largely unknown.

Correction: Neuronal Hyperactivity Disturbs ATP Microgradients, Impairs Microglial Motility, and Reduces Phagocytic Receptor Expression Triggering Apoptosis/Microglial Phagocytosis Uncoupling.

[This corrects the article DOI: 10.1371/journal.pbio.

Correction: Neuronal Hyperactivity Disturbs ATP Microgradients, Impairs Microglial Motility, and Reduces Phagocytic Receptor Expression Triggering Apoptosis/Microglial Phagocytosis Uncoupling.

[This corrects the article DOI: 10.1371/journal.pbio.

Neuronal Hyperactivity Disturbs ATP Microgradients, Impairs Microglial Motility, and Reduces Phagocytic Receptor Expression Triggering Apoptosis/Microglial Phagocytosis Uncoupling.

Phagocytosis is essential to maintain tissue homeostasis in a large number of inflammatory and autoimmune diseases, but its role in the diseased brain is poorly explored. Recent findings suggest that in the adult hippocampal neurogenic niche, where the excess of newborn cells undergo apoptosis in physiological conditions, phagocytosis is efficiently executed by surveillant, ramified microglia. To test whether microglia are efficient phagocytes in the diseased brain as well, we confronted them with a series of apoptotic challenges and discovered a generalized response.

Microglia across the lifespan: from origin to function in brain development, plasticity and cognition.

Microglia are the only immune cells that permanently reside in the central nervous system (CNS) alongside neurons and other types of glial cells. The past decade has witnessed a revolution in our understanding of their roles during normal physiological conditions. Cutting-edge techniques revealed that these resident immune cells are critical for proper brain development, actively maintain health in the mature brain, and rapidly adapt their function to physiological or pathophysiological needs.

Non-Neuronal Cells Are Required to Mediate the Effects of Neuroinflammation: Results from a Neuron-Enriched Culture System.

Chronic inflammation is associated with activated microglia and reactive astrocytes and plays an important role in the pathogenesis of neurodegenerative diseases such as Alzheimer's. Both in vivo and in vitro studies have demonstrated that inflammatory cytokine responses to immune challenges contribute to neuronal death during neurodegeneration. In order to investigate the role of glial cells in this phenomenon, we developed a modified method to remove the non-neuronal cells in primary cultures of E16.

Individual Cytokines Modulate the Neurological Symptoms of ATM Deficiency in a Region Specific Manner.

Ataxia-telangiectasia (A-T) is a multisystemic neurodegenerative disease of childhood caused by the absence of functional ATM (A-T mutated) protein. The cerebellar cortex has the most obvious neuropathology, yet cells in other brain regions are also abnormal. A-T mouse models have been produced that replicate much, though not all, of the complex A-T phenotype.

Correction: The Interaction of the Atm Genotype with Inflammation and Oxidative Stress.

[This corrects the article DOI: 10.1371/journal.pone.

The interaction of the atm genotype with inflammation and oxidative stress.

In ataxia-telangiectasia (A-T) the death of neurons is associated with the loss of neuronal cell cycle control. In most Atm(-/-) mouse models, however, these cell cycle anomalies are present but the phenotype of neuronal cell loss found in humans is not. Mouse Atm(-/-) neurons re-enter a cell cycle and replicate their DNA, but they do not die--even months after initiating the cycle.