1,664 research outputs found

    Nlrp6 promotes recovery after peripheral nerve injury independently of inflammasomes

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    Background: NOD-like receptors (Nlrs) are key regulators of immune responses during infection and autoimmunity. A subset of Nlrs assembles inflammasomes, molecular platforms that are activated in response to endogenous danger and microbial ligands and that control release of interleukin (IL)-1 beta and IL-18. However, their role in response to injury in the nervous system is less understood. Methods: In this study, we investigated the expression profile of major inflammasome components in the peripheral nervous system (PNS) and explored the physiological role of different Nlrs upon acute nerve injury in mice. Results: While in basal conditions, predominantly members of NOD-like receptor B (Nlrb) subfamily (NLR family, apoptosis inhibitory proteins (NAIPs)) and Nlrc subfamily (ICE-protease activating factor (IPAF)/NOD) are detected in the sciatic nerve, injury causes a shift towards expression of the Nlrp family. Sterile nerve injury also leads to an increase in expression of the Nlrb subfamily, while bacteria trigger expression of the Nlrc subfamily. Interestingly, loss of Nlrp6 led to strongly impaired nerve function upon nerve crush. Loss of the inflammasome adaptor apoptosis-associated speck-like protein containing a CARD (ASC) and effector caspase-1 and caspase-11 did not affect sciatic nerve function, suggesting that Nlrp6 contributed to recovery after peripheral nerve injury independently of inflammasomes. In line with this, we did not detect release of mature IL-1 beta upon acute nerve injury despite potent induction of pro-IL-1 beta and inflammasome components Nlrp3 and Nlrp1. However, Nlrp6 deficiency was associated with increased pro-inflammatory extracellular regulated MAP kinase (ERK) signaling, suggesting that hyperinflammation in the absence of Nlrp6 exacerbated peripheral nerve injury. Conclusions: Together, our observations suggest that Nlrp6 contributes to recovery from peripheral nerve injury by dampening inflammatory responses independently of IL-1 beta and inflammasomes

    NOD2 and inflammation: current insights

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    The nucleotide-binding oligomerization domain (NOD) protein, NOD2, belonging to the intracellular NOD-like receptor family, detects conserved motifs in bacterial peptidoglycan and promotes their clearance through activation of a proinflammatory transcriptional program and other innate immune pathways, including autophagy and endoplasmic reticulum stress. An inactive form due to mutations or a constitutive high expression of NOD2 is associated with several inflammatory diseases, suggesting that balanced NOD2 signaling is critical for the maintenance of immune homeostasis. In this review, we discuss recent developments about the pathway and mechanisms of regulation of NOD2 and illustrate the principal functions of the gene, with particular emphasis on its central role in maintaining the equilibrium between intestinal microbiota and host immune responses to control inflammation. Furthermore, we survey recent studies illustrating the role of NOD2 in several inflammatory diseases, in particular, inflammatory bowel disease, of which it is the main susceptibility gene

    Fiery Connections: Macrophage-Mediated Inflammation, the Journey from Obesity to Type 2 Diabetes Mellitus and Diabetic Kidney Disease.

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    The high prevalence of diabetes mellitus (DM) poses a significant public health challenge, with diabetic kidney disease (DKD) as one of its most serious consequences. It has become increasingly clear that type 2 DM (T2D) and the complications of DKD are not purely metabolic disorders. This review outlines emerging evidence related to the step-by-step contribution of macrophages to the development and progression of DKD in individuals who specifically develop T2D as a result of obesity. The macrophage is a prominent inflammatory cell that contributes to obesity, where adipocyte hypertrophy leads to macrophage recruitment and eventually to the expansion of adipose tissue. The recruited macrophages secrete proinflammatory cytokines, which cause systemic inflammation, glucose dysregulation, and insulin sensitivity, ultimately contributing to the development of T2D. Under such pathological changes, the kidney is susceptible to elevated glucose and thereby activates signaling pathways that ultimately drive monocyte recruitment. In particular, the early recruitment of proinflammatory macrophages in the diabetic kidney produces inflammatory cytokines/chemokines that contribute to inflammation and tissue damage associated with DKD pathology. Macrophage activation and recruitment are crucial inciting factors that also persist as DKD progresses. Thus, targeting macrophage activation and function could be a promising therapeutic approach, potentially offering significant benefits for managing DKD at all stages of progression

    The Potency of Camellia Sinensis L. to Reduce Proinflammatory Cytokine Levels in the Acute Respiratory Distress Syndrome Rat Model

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    This study was conducted in order to ascertain how green tea extract (GTE) could affect inflammatory markers, including level of interleukin-(IL)-12, IL-18 of serum and lung, tumor necrosis factor (TNF)-α, gene expression of NLR family-pyrin-domain containing 3 (NLRP3) of lung, nuclear factor kappa B (NF-κB), lung histopathology, and IL-6 expression of lung tissue in lipopolysaccharide (LPS)-treated rats as ARDS animal model. Rats were given GTE at dosages of 0, 50, 400, 800 mg/kg of body weight for 28 days to boost their immune systems. The rats were then stimulated with LPS (5 g/kg of BW) and after that continued to receive GTE for 28 days. Levels of serum or lung IL-18, IL-12, TNF-α, were measured using the ELISA method; expression of lung NF-κB and NLRP3 was measured by qRT-PCR; immunohistochemistry (IHC) was implemented to assess lung IL-6 expression; and lung histopathology was evaluated through the bleeding, inflammation, and alveolus scores. GTE had the ability to lower serum IL-18, lung TNF-α, and lung IL-12 levels; suppress the lung gene expression of NF-κB, NLRP-3, IL-6 expression; and improve lung histopathology. Green tea extract inhibited inflammation in the ARDS rat model by decreasing the proinflammatory cytokine level and proinflammatory gene expression

    The Potency of Camellia Sinensis L. to Reduce Proinflammatory Cytokine Levels in the Acute Respiratory Distress Syndrome Rat Model

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    This study was conducted in order to ascertain how green tea extract (GTE) could affect inflammatory markers, including level of interleukin-(IL)-12, IL-18 of serum and lung, tumor necrosis factor (TNF)-α, gene expression of NLR family-pyrin-domain containing 3 (NLRP3) of lung, nuclear factor kappa B (NF-κB), lung histopathology, and IL-6 expression of lung tissue in lipopolysaccharide (LPS)-treated rats as ARDS animal model. Rats were given GTE at dosages of 0, 50, 400, 800 mg/kg of body weight for 28 days to boost their immune systems. The rats were then stimulated with LPS (5 g/kg of BW) and after that continued to receive GTE for 28 days. Levels of serum or lung IL-18, IL-12, TNF-α, were measured using the ELISA method; expression of lung NF-κB and NLRP3 was measured by qRT-PCR; immunohistochemistry (IHC) was implemented to assess lung IL-6 expression; and lung histopathology was evaluated through the bleeding, inflammation, and alveolus scores. GTE had the ability to lower serum IL-18, lung TNF-α, and lung IL-12 levels; suppress the lung gene expression of NF-κB, NLRP-3, IL-6 expression; and improve lung histopathology. Green tea extract inhibited inflammation in the ARDS rat model by decreasing the proinflammatory cytokine level and proinflammatory gene expression

    Identification of mutations in the PYRIN-containing NLR genes (NLRP) in head and neck squamous cell carcinoma

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    Head and Neck Squamous Cell Carcinoma (HNSCC) encompasses malignancies that arise in the mucosa of the upper aerodigestive tract. Recent high throughput DNA sequencing revealed HNSCC genes mutations that contribute to several cancer cell characteristics, including dysregulation of cell proliferation and death, intracellular proinflammatory signaling, and autophagy. The PYRIN-domain containing NLR (Nucleotide-binding domain, Leucine rich Repeats - containing) proteins have recently emerged as pivotal modulators of cell death, autophagy, inflammation, and metabolism. Their close physiologic association with cancer development prompted us to determine whether mutations within the NLRP (PYRIN-containing NLR ) gene family were associated with HNSCC genome instability and their clinicopathologic correlations. Catastrophic mutational events underlie cancer cell genome instability and mark a point-of-no-return in cancer cell development and generation of heterogeneity. The mutation profiles of 62 patients with primary conventional type HNSCC excluding other histologic variants were analyzed. Associations were tested using Fisher's Exact test or Mann-Whitney U test. Mutations in NLRP were associated with elevated genome instability as characterized by higher mutation rates. Clinically, NLRP mutations were more frequently found in HNSCC arising in the floor of mouth (50.0%) in comparison with HNSCC at other head and neck locations (14.8%). These mutations were clustered at the leucine rich repeats region of NLRP proteins, and affected NLRP genes were mostly localized at chromosomes 11p15.4 and 19q13.42-19q13.43. Twenty novel NLRP mutations were identified in HNSCC, and mutations in this group of genes were correlated with increased cancer cell genome mutation rates, and such features could be a potential molecular biomarker of HNSCC genome instability. © 2014 Lei et al

    Role of Innate Immunity in Diabetes and Metabolism: Recent Progress in the Study of Inflammasomes

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    Type 1 diabetes is one of the classical examples of organ- specific autoimmune diseases characterized by lymphocytic infiltration or inflammation in pancreatic islets called 'insulitis'. In contrast, type 2 diabetes has been traditionally regarded as a metabolic disorder with a pathogenesis that is totally different from that of type 1 diabetes. However, recent investigation has revealed contribution of chronic inflammation in the pathogenesis of type 2 diabetes. In addition to type 2 diabetes, the role of chronic inflammation is being appreciated in a wide variety of metabolic disorders such as obesity, metabolic syndrome, and atherosclerosis. In this review, we will cover the role of innate immunity in the pathogenesis of metabolic disorders with an emphasis on NLRP3

    Evolution and functional divergence of NLRP genes in mammalian reproductive systems

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    <p>Abstract</p> <p>Background</p> <p>NLRPs (Nucleotide-binding oligomerization domain, Leucine rich Repeat and Pyrin domain containing Proteins) are members of NLR (Nod-like receptors) protein family. Recent researches have shown that <it>NLRP </it>genes play important roles in both mammalian innate immune system and reproductive system. Several of <it>NLRP </it>genes were shown to be specifically expressed in the oocyte in mammals. The aim of the present work was to study how these genes evolved and diverged after their duplication, as well as whether natural selection played a role during their evolution.</p> <p>Results</p> <p>By using <it>in silico </it>methods, we have evaluated the evolution and functional divergence of <it>NLRP </it>genes, in particular of mouse reproduction-related <it>Nlrp </it>genes. We found that (1) major <it>NLRP </it>genes have been duplicated before the divergence of mammals, with certain lineage-specific duplications in primates (<it>NLRP7 </it>and <it>11</it>) and in rodents (<it>Nlrp1</it>, <it>4 </it>and <it>9 </it>duplicates); (2) tandem duplication events gave rise to a mammalian reproduction-related <it>NLRP </it>cluster including <it>NLRP2</it>, <it>4</it>, <it>5</it>, <it>7</it>, <it>8</it>, <it>9</it>, <it>11</it>, <it>13 </it>and <it>14 </it>genes; (3) the function of mammalian oocyte-specific <it>NLRP </it>genes (<it>NLRP4</it>, <it>5</it>, <it>9 </it>and <it>14</it>) might have diverged during gene evolution; (4) recent segmental duplications concerning <it>Nlrp4 </it>copies and vomeronasal 1 receptor encoding genes (<it>V1r</it>) have been undertaken in the mouse; and (5) duplicates of <it>Nlrp4 </it>and <it>9 </it>in the mouse might have been subjected to adaptive evolution.</p> <p>Conclusion</p> <p>In conclusion, this study brings us novel information on the evolution of mammalian reproduction-related <it>NLRPs</it>. On the one hand, <it>NLRP </it>genes duplicated and functionally diversified in mammalian reproductive systems (such as <it>NLRP4</it>, <it>5</it>, <it>9 </it>and <it>14</it>). On the other hand, during evolution, different lineages adapted to develop their own <it>NLRP </it>genes, particularly in reproductive function (such as the specific expansion of <it>Nlrp4 </it>and <it>Nlrp9 </it>in the mouse).</p

    Innate immunity and neuroinflammation

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    Copyright © 2013 Abhishek Shastri et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Inflammation of central nervous system (CNS) is usually associated with trauma and infection. Neuroinflammation occurs in close relation to trauma, infection, and neurodegenerative diseases. Low-level neuroinflammation is considered to have beneficial effects whereas chronic neuroinflammation can be harmful. Innate immune system consisting of pattern-recognition receptors, macrophages, and complement system plays a key role in CNS homeostasis following injury and infection. Here, we discuss how innate immune components can also contribute to neuroinflammation and neurodegeneration
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