The NLRP1 inflammasome in human skin and beyond

Inflammasomes represent a group of protein complexes that contribute to host defense against pathogens and repair processes upon the induction of inflammation. However, aberrant and chronic inflammasome activation underlies the pathology of numerous common inflammatory diseases. Inflammasome assembly causes activation of the protease caspase-1 which in turn activates proinflammatory cytokines and induces a lytic type of cell death termed pyroptosis. Although NLRP1 (NACHT, leucine-rich repeat and pyrin domain containing 1) was the first inflammasome sensor, described almost 20 years ago, the molecular mechanisms underlying its activation and the resulting downstream events are incompletely understood. This is partially a consequence of the poor conservation of the NLRP1 pathway between human and mice. Moreover, recent evidence demonstrates a complex and multi-stage mechanism of NLRP1 inflammasome activation. In contrast to other inflammasome sensors, NLRP1 possesses protease activity required for proteolytic self-cleavage and activation mediated by the function-to-find domain (FIIND). CARD8 is a second FIIND protein and is expressed in humans but not in mice. In immune cells and AML (acute myeloid leukemia) cells, the anti-cancer drug talabostat induces CARD8 activation and causes caspase-1-dependent pyroptosis. In contrast, in human keratinocytes talabostat induces NLRP1 activation and massive proinflammatory cytokine activation. NLRP1 is regarded as the principal inflammasome sensor in human keratinocytes and UVB radiation induces its activation, which is believed to underlie the induction of sunburn. Moreover, gain-of-function mutations of NLRP1 cause inflammatory skin syndromes and a predisposition for the development of skin cancer. SNPs (single nucleotide polymorphisms) of NLRP1 are associated with several (auto)inflammatory diseases with a major skin phenotype, such as psoriasis or vitiligo. Here, we summarize knowledge about NLRP1 with emphasis on its role in human keratinocytes and skin. Due to its accessibility, pharmacological targeting of NLRP1 activation in epidermal keratinocytes represents a promising strategy for the treatment of the numerous patients suffering from NLRP1-dependent inflammatory skin conditions and cancer

NLRP1 in Cutaneous SCCs: An Example of the Complex Roles of Inflammasomes in Cancer Development

Protein complexes termed inflammasomes ensure tissue protection from pathogenic and sterile stressors by induction of inflammation. This is mediated by different caspase-1-induced downstream pathways, including activation of the pro-inflammatory cytokines proIL-1β and -18, induction of a lytic type of cell death, and regulation of the release of other pro-inflammatory molecules. Aberrant inflammasome activation underlies the pathology of numerous (auto)inflammatory diseases. Furthermore, inflammasomes support or suppress tumor development in a complex cell-type- and stage-dependent manner. In human keratinocytes and skin, NLRP1 is the central inflammasome sensor activated by cellular perturbation induced, for example, by UVB radiation. UVB represents the main inducer of skin cancer, which is the most common type of malignancy in humans. Recent evidence demonstrates that activation of NLRP1 in human skin supports the development of cutaneous squamous cell carcinomas (cSCCs) by inducing skin inflammation. In contrast, the NLRP1 inflammasome pathway is restrained in established cSCCs, suggesting that, at this stage, the protein complex has a tumor suppressor role. A better understanding of the complex functions of NLRP1 in the development of cSCCs and in general of inflammasomes in cancer might pave the way for novel strategies for cancer prevention and therapy. These strategies might include stage-specific modulation of inflammasome activation or its downstream pathways by mono- or combination therapy

High p62 expression suppresses the NLRP1 inflammasome and increases stress resistance in cutaneous SCC cells

NLRP1 is the primary inflammasome sensor in human keratinocytes. Sensing of UVB radiation by NLRP1 is believed to underlie the induction of sunburn. Although constitutive NLRP1 activation causes skin inflammation and predisposes patients to the development of cutaneous SCCs, the NLRP1 pathway is suppressed in established SCCs. Here, we identified high levels of the autophagy receptor p62 in SCC cells lines and SCC tumors. Increased NF-κB activity in SCC cells causes p62 up-regulation. Suppression of p62 expression rescues UVB-induced NLRP1 inflammasome activation in early-stage SCC cells. p62 expression protects SCC cells from cytotoxic drugs, whereas NLRP1 sensitizes them. In summary, we identify p62 as a novel negative regulator of the NLRP1 inflammasome in human cutaneous SCC cells, in which suppression of NLRP1 by increased levels of p62 supports stress resistance of skin cancer cells

NLRP1 Inflammasome Activation in Keratinocytes: Increasing Evidence of Important Roles in Inflammatory Skin Diseases and Immunity

In 2007, it was shown that DNA sequence variants of the human NLRP1 gene are associated with autoimmune and autoinflammatory diseases affecting mainly the skin. However, at that time, the underlying cellular and molecular mechanisms were poorly characterized. Meanwhile, increasing evidence suggests that the NLRP1 inflammasome expressed by keratinocytes not only plays a part in the pathology of common inflammatory skin diseases and cancer development but also contributes to skin immunity. Understanding the mechanisms regulating NLRP1 activation in keratinocytes and the downstream events in human skin might pave the way for developing novel strategies for treating patients suffering from NLRP1-mediated skin diseases

The Language of Pain in the Hypermobile Ehlers–Danlos Syndrome: Metaphors as a Key to Understanding the Experience of Pain and as a Rehabilitation Tool

Ehlers-Danlos syndromes are a heterogeneous group of Heritable Connective Tissue Disorders characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Among the different types, the hypermobile Ehlers-Danlos syndrome is the most frequent and includes generalized joint hypermobility as the major diagnostic criterion. Joint hypermobility in hypermobile Ehlers-Danlos syndrome is often associated with pain that does not always allow the use of effective pain-reducing treatments. Patients with hEDS constantly describe their pain in detail. Eighty-nine patients with hEDS diagnoses were recruited and evaluated. They were asked to describe their pain in writing. The texts were examined through Linguistic Inquiry and Word Count. Correlational analyses were conducted between pain perception and language. A comparison of high/low pain perception and the quality of metaphors was carried out. The results showed that language quality varies depending on how much pain is perceived. The greater the pain is perceived, the lesser the positive effects and the greater the negative effects and dehumanizing metaphors are being used. Moreover, a greater pain seems to be related to a verbal experience of greater isolation and less self-care. In conclusion, the use of metaphors is a useful tool for examining illness experience and may help clinicians in the rehabilitation program

Short-term and long-term plasticity at corticostriatal synapses: implications for learning and memor

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New insights on binary black hole formation channels after GWTC-2: young star clusters versus isolated binaries

With the recent release of the second gravitational-wave transient catalogue (GWTC-2), which introduced dozens of new detections, we are at a turning point of gravitational wave astronomy, as we are now able to directly infer constraints on the astrophysical population of compact objects. Here, we tackle the burning issue of understanding the origin of binary black hole (BBH) mergers. To this effect, we make use of state-of-the-art population synthesis and N-body simulations, to represent two distinct formation channels: BBHs formed in the field (isolated channel) and in young star clusters (dynamical channel). We then use a Bayesian hierarchical approach to infer the distribution of the mixing fraction $f$, with $f=0$ ($f=1$) in the pure dynamical (isolated) channel. %that controls the proportion of isolated and dynamical BBHs. We explore the effects of additional hyper-parameters of the model, such as the spread in metallicity $\sigma_{\text{Z}}$ and the parameter $\sigma_{\text{sp}}$, describing the distribution of spin magnitudes. We find that the dynamical model is slightly favoured with a median value of $f=0.26$, when $\sigma_{\text{sp}}=0.1$ and $\sigma_{\text{Z}}=0.4$. Models with higher spin magnitudes tend to strongly favour dynamically formed BBHs ($f\le{}0.1$ if $\sigma_{\text{sp}}=0.3$). Furthermore, we show that hyper-parameters controlling the rates of the model, such as $\sigma_{\rm Z}$, have a large impact on the inference of the mixing fraction, which rises from $0.18$ to $0.43$ when we increase $\sigma_{\text{Z}}$ from 0.2 to 0.6, for a fixed value of $\sigma_{\text{sp}}=0.1$. Finally, our current set of observations is better described by a combination of both formation channels, as a pure dynamical scenario is excluded at the $99\%$ credible interval, except when the spin magnitude is high.Comment: 13 pages, 10 figures, 2 tables, published in MNRA

Il settore dell'open source: strategie, minacce, opportunita' nel mercato italiano

Cap.1 - Introduzione al mondo open source\ud Un po' di storia. Il movimento free software. Il modello Open Source. Tutela giuridica del software. Le licenze commerciali e le licenze open source.\ud Cap.2 - Il business dell'open source.\ud Premessa. Il mercato dell'OS. La metodologia utilizzata. Engineering sul mercato. Le funzioni d'uso. I principali prodotti open source. I clienti: la pubblica amministrazione. \ud Cap.3 - Il mostro modello di business\ud Scelta del modello di riferimento. Analisi della concorrenza allargat

Fragile X mental retardation protein (FMRP) and metabotropic glutamate receptor subtype 5 (mGlu5) control stress granule formation in astrocytes

Fragile X syndrome (FXS) is a common form of intellectual disability and autism caused by the lack of Fragile X Mental Retardation Protein (FMRP), an RNA-binding protein involved in RNA transport and protein synthesis. Upon cellular stress, global protein synthesis is blocked and mRNAs are recruited into stress granules (SGs), together with RNA-binding proteins including FMRP. Activation of group-I metabotropic glutamate (mGlu) receptors stimulates FMRP-mediated mRNA transport and protein synthesis, but their role in SGs formation is unexplored. To this aim, we pre-treated wild type (WT) and Fmr1 knockout (KO) cultured astrocytes with the group-I-mGlu receptor agonist (S)-3,5-Dihydroxyphenylglycine (DHPG) and exposed them to sodium arsenite (NaAsO2), a widely used inducer of SGs formation. In WT cultures the activation of group-I mGlu receptors reduced SGs formation and recruitment of FMRP into SGs, and also attenuated phosphorylation of eIF2α, a key event crucially involved in SGs formation and inhibition of protein synthesis. In contrast, Fmr1 KO astrocytes, which exhibited a lower number of SGs than WT astrocytes, did not respond to agonist stimulation. Interestingly, the mGlu5 receptor negative allosteric modulator (NAM) 2-methyl-6-(phenylethynyl)pyridine (MPEP) antagonized DHPG-mediated SGs reduction in WT and reversed SGs formation in Fmr1 KO cultures. Our findings reveal a novel function of mGlu5 receptor as modulator of SGs formation and open new perspectives for understanding cellular response to stress in FXS pathophysiology

A2A adenosine receptor antagonists protect the striatum against rotenone-induced neurotoxicity.

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