Role of the NLR gene family members in neuroinflammation and demyelination in the CNS

Sterile inflammation in the brain is recognized as a key component of many neurological diseases including multiple sclerosis (MS), amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease. An understanding of the mechanisms by which neuroinflammation occurs and the molecular mediators involved in this process is necessary for identification of potential therapeutic targets. The NLR gene family members have emerged as important regulators of immunity and inflammation due to their genetic linkage to several human immunologic diseases. In this study, our goal was to ascertain the role of NLR dependent cellular pathways in neuroinflammation, demyelination and remyelination. An in vivo cuprizone-induced mouse model of demyelination and remyelination along with ex vivo primary cell culture assays were utilized. Mice deficient in NLRP3 (Nlrp3-/-), IL-1[beta] (IL-1[beta]-/-), caspase-1 (casp1-/-), P2X7R (P2X7R-/-), IL-18 (IL-18-/-) and NLRC4 (Nlrc4-/-) were used for these studies

Inflammasome-Associated Nucleotide-Binding Domain, Leucine-Rich Repeat Proteins and Inflammatory Diseases

The nucleotide-binding domain, leucine-rich repeat (NLR) proteins are a recently discovered family of intracellular pathogen and danger signal sensors. NLRs have emerged as important contributors to innate immunity in animals. The physiological impact of these genes is increasingly evident, underscored by the genetic association of variant family members with an array of inflammatory diseases. The association of mutations in NLR genes with autoinflammatory diseases indicates an important function of these genes in inflammation in vivo. This review summarizes the role of the inflammasome NLR proteins in innate immunity and inflammatory diseases and explores the possible utility of some of these NLRs as pharmacological targets

Dopamine induces functional extracellular traps in microglia

Dopamine (DA) plays many roles in the brain, especially in movement, motivation, and reinforcement of behavior; however, its role in regulating innate immunity is not clear. Here, we show that DA can induce DNA-based extracellular traps in primary, adult, human microglia and BV2 microglia cell line. These DNA-based extracellular traps are formed independent of reactive oxygen species, actin polymerization, and cell death. These traps are functional and capture fluorescein (FITC)-tagged Escherichia coli even when reactive oxygen species production or actin polymerization is inhibited. We show that microglial extracellular traps are present in Glioblastoma multiforme. This is crucial because Glioblastoma multiforme cells are known to secrete DA. Our findings demonstrate that DA plays a significant role in sterile neuro-inflammation by inducing microglia extracellular traps

NLR members NLRC4 and NLRP3 mediate sterile inflammasome activation in microglia and astrocytes

Inflammation in the brain accompanies several high-impact neurological diseases including multiple sclerosis (MS), stroke, and Alzheimer’s disease. Neuroinflammation is sterile, as damage-associated molecular patterns rather than microbial pathogens elicit the response. The inflammasome, which leads to caspase-1 activation, is implicated in neuroinflammation. In this study, we reveal that lysophosphatidylcholine (LPC), a molecule associated with neurodegeneration and demyelination, elicits NLRP3 and NLRC4 inflammasome activation in microglia and astrocytes, which are central players in neuroinflammation. LPC-activated inflammasome also requires ASC (apoptotic speck containing protein with a CARD), caspase-1, cathepsin-mediated degradation, calcium mobilization, and potassium efflux but not caspase-11. To study the physiological relevance, Nlrc4 −/− and Nlrp3 −/− mice are studied in the cuprizone model of neuroinflammation and demyelination. Mice lacking both genes show the most pronounced reduction in astrogliosis and microglial accumulation accompanied by decreased expression of the LPC receptor G2A, whereas MS patient samples show increased G2A. These results reveal that NLRC4 and NLRP3, which normally form distinct inflammasomes, activate an LPC-induced inflammasome and are important in astrogliosis and microgliosis

A Survey of COVID-19 Contact Tracing Apps

The recent outbreak of COVID-19 has taken the world by surprise, forcing lockdowns and straining public health care systems. COVID-19 is known to be a highly infectious virus, and infected individuals do not initially exhibit symptoms, while some remain asymptomatic. Thus, a non-negligible fraction of the population can, at any given time, be a hidden source of transmissions. In response, many governments have shown great interest in smartphone contact tracing apps that help automate the difficult task of tracing all recent contacts of newly identified infected individuals. However, tracing apps have generated much discussion around their key attributes, including system architecture, data management, privacy, security, proximity estimation, and attack vulnerability. In this article, we provide the first comprehensive review of these much-discussed tracing app attributes. We also present an overview of many proposed tracing app examples, some of which have been deployed countrywide, and discuss the concerns users have reported regarding their usage. We close by outlining potential research directions for next-generation app design, which would facilitate improved tracing and security performance, as well as wide adoption by the population at large.Comment: Paper has been accepted for publication in IEEE Access. Currently available on IEEE ACCESS early access (see DOI

Fatty acid–induced NLRP3-ASC inflammasome activation interferes with insulin signaling

High-fat diet (HFD) and inflammation are key contributors to insulin resistance and type 2 diabetes (T2D). Interleukin (IL)-1β plays a role in insulin resistance; yet, how IL-1β is induced by fatty acid with HFD, and how this alters insulin signaling is unclear. We show that the saturated fatty acid, palmitate, but not unsaturated oleate, induces the activation of NLRP3-PYCARD inflammasome, causing caspase-1, IL-1β, and IL-18 production. This involves mitochondrial reactive oxygen species and the AMP-activated protein kinase and ULK1 autophagy signaling cascade. Inflammasome activation in hematopoietic cells impairs insulin signaling in several target tissues to reduce glucose tolerance and insulin sensitivity. Furthermore, IL-1β affects insulin sensitivity via TNF-independent and dependent pathways. These findings provide insights into the association of inflammation, diet and T2D

Plexin-D1 Is a Novel Regulator of Germinal Centers and Humoral Immune Responses

Long-lived humoral immune responses depend upon the generation of memory B cells and long-lived plasma cells during the germinal center (GC) reaction. These memory compartments, characterized by class-switched IgG and high-affinity Abs, are the basis for successful vaccination. We report that a new member of the plexin family of molecules, plexin-D1, controls the GC reaction and is required for secondary humoral immune responses. Plexin-D1 was not required for B cell maturation, marginal zone precursor development, dark and light zone formation, Igλ+ and Igκ+ B cell skewing, B1/B2 development, and the initial extrafollicular response. Plexin-D1 expression was increased following B cell activation, and PlxnD1−/− mice exhibited defective GC reactions during T-dependent immune activation. PlxnD1−/− B cells showed a defect in migration toward the GC chemokines, CXCL12, CXCL13, and CCL19. Accordingly, PlxnD1−/− mice exhibited defective production of IgG1 and IgG2b, but not IgG3 serum Ab, accompanied by reductions in long-lived bone marrow plasmacytes and recall humoral memory responses. These data show a new role for immune plexins in the GC reaction and generation of immunologic memory

The Inflammasome Sensor, NLRP3, Regulates CNS Inflammation and Demyelination via Caspase-1 and Interleukin-18

Inflammation is increasingly recognized as an important contributor to a host of CNS disorders; however, its regulation in the brain is not well delineated. Nucleotide-binding domain, leucine-rich repeat, pyrin domain containing 3 (NLRP3) is a key component of the inflammasome complex, which also includes ASC (apoptotic speck-containing protein with a card) and procaspase-1. Inflammasome formation can be triggered by membrane P2

MyD88 provides a protective role in long-term radiation-induced lung injury

The role of innate immune regulators is investigated in injury sustained from irradiation as in the clinic for cancer treatment or from a nuclear incident. The protective benefits of flagellin signaling through Toll-like receptors (TLR) in an irradiation setting warrant study of a key intracellular adaptor of TLR signaling, namely Myeloid differentiation primary response factor 88 (MyD88). The role of MyD88 in regulating innate immunity and Nuclear factor kappa-B (NF-κB)-activated responses targets this critical factor for influencing injury and recovery as well as maintaining immune homeostasis