scholarly journals NLRP3 Inflammasome and Allergic Contact Dermatitis: A Connection to Demystify

Pharmaceutics ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 867
Author(s):  
Ana Isabel Sebastião ◽  
Isabel Ferreira ◽  
Gonçalo Brites ◽  
Ana Silva ◽  
Bruno Miguel Neves ◽  
...  
Keyword(s):  
Contact Dermatitis ◽  
Allergic Contact Dermatitis ◽  
Nlrp3 Inflammasome ◽  
Molecular Mechanisms ◽  
Alternative Methods ◽  
Inflammasome Activation ◽  
Pyrin Domain ◽  
And Migration ◽  
Novel Therapeutic Strategies ◽  
Allergic Contact

Allergic contact dermatitis is a common occupational disease that manifests as a cell-mediated hypersensitivity reaction following skin exposure to small reactive chemicals termed haptens. Haptens penetrate the stratum corneum and covalently modify proteins in the epidermis, inducing intracellular stress, which further leads to the release of damage-associated molecular patterns (DAMPs), such as uric acid, reactive oxygen species, hyaluronic acid fragments and extracellular adenosine triphosphate (ATP). These DAMPs are recognized by pattern recognition receptors (PRRs) in innate immune cells, namely dendritic cells (DCs), leading to their maturation and migration to the draining lymph nodes where they activate naïve T lymphocytes. Among all PRRs, several studies emphasize the role of NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome on the allergic contact dermatitis (ACD) sensitization phase. However, skin allergens—danger signals—NLRP3 inflammasome axis is yet to be completely elucidated. Therefore, in this review, we sought to discuss the molecular mechanisms underlying DAMPs release and NLRP3 inflammasome activation triggered by skin allergens. The elucidation of these key events might help to identify novel therapeutic strategies for ACD, as well as the development of nonanimal alternative methods for the identification and potency categorization of skin sensitizers.

scholarly journals Targeting NLRP3 Inflammasome Activation in Severe Asthma

2019 ◽  
Vol 8 (10) ◽  
pp. 1615 ◽  
Author(s):  
Efthymia Theofani ◽  
Maria Semitekolou ◽  
Ioannis Morianos ◽  
Konstantinos Samitas ◽  
Georgina Xanthou
Keyword(s):  
Severe Asthma ◽  
Nlrp3 Inflammasome ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Pulmonary Inflammation ◽  
Airflow Obstruction ◽  
Inflammasome Activation ◽  
Pyrin Domain ◽  
Nlrp3 Inflammasome Activation ◽  
Reversible Airflow Obstruction

Severe asthma (SA) is a chronic lung disease characterized by recurring symptoms of reversible airflow obstruction, airway hyper-responsiveness (AHR), and inflammation that is resistant to currently employed treatments. The nucleotide-binding oligomerization domain-like Receptor Family Pyrin Domain Containing 3 (NLRP3) inflammasome is an intracellular sensor that detects microbial motifs and endogenous danger signals and represents a key component of innate immune responses in the airways. Assembly of the NLRP3 inflammasome leads to caspase 1-dependent release of the pro-inflammatory cytokines IL-1β and IL-18 as well as pyroptosis. Accumulating evidence proposes that NLRP3 activation is critically involved in asthma pathogenesis. In fact, although NLRP3 facilitates the clearance of pathogens in the airways, persistent NLRP3 activation by inhaled irritants and/or innocuous environmental allergens can lead to overt pulmonary inflammation and exacerbation of asthma manifestations. Notably, administration of NLRP3 inhibitors in asthma models restrains AHR and pulmonary inflammation. Here, we provide an overview of the pathophysiology of SA, present molecular mechanisms underlying aberrant inflammatory responses in the airways, summarize recent studies pertinent to the biology and functions of NLRP3, and discuss the role of NLRP3 in the pathogenesis of asthma. Finally, we contemplate the potential of targeting NLRP3 as a novel therapeutic approach for the management of SA.

scholarly journals Haploinsufficiency of A20 impairs protein-protein interactome and leads into caspase-8-dependent enhancement of NLRP3 inflammasome activation

2018 ◽  
Author(s):  
Kristiina Rajamäki ◽  
Salla Keskitalo ◽  
Mikko Seppänen ◽  
Outi Kuismin ◽  
Paula Vähäsalo ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Immune Cells ◽  
Nlrp3 Inflammasome ◽  
Molecular Mechanisms ◽  
Luciferase Reporter ◽  
Caspase 8 ◽  
Inflammasome Activation ◽  
Loss Of Function ◽  
Pyrin Domain ◽  
Protein Interactome

ABSTRACTObjectivesTNFAIP3 encodes A20 that negatively regulates nuclear factor kappa light chain enhancer of activated B cells (NF-κB), the major transcription factor coordinating inflammatory gene expression. TNFAIP3 polymorphisms have been linked with a spectrum of inflammatory and autoimmune diseases and recently, loss-of-function mutations in A20 were found to cause a novel inflammatory disease ‘haploinsufficiency of A20’ (HA20). Here we describe a family with HA20 caused by a novel TNFAIP3 loss-of-function mutation and elucidate the upstream molecular mechanisms linking HA20 to dysregulation of NF-κB and the related inflammasome pathway.MethodsNF-κB activation was studied in a mutation-expressing cell line using luciferase reporter assay. Physical and close-proximity protein-protein interactions of wild-type and TNFAIP3 p.(Lys91*) mutant A20 were analyzed using mass spectrometry. NF-κB –dependent transcription, cytokine secretion, and inflammasome activation were compared in immune cells of the HA20 patients and control subjects.ResultsThe protein-protein interactome of p.(Lys91*) mutant A20 was severely impaired, including inter-actions with proteins regulating NF-κB activation, DNA repair responses, and the NLR family pyrin domain containing 3 (NLRP3) inflammasome. The p.(Lys91*) mutant A20 failed to suppress NF-κB signaling, which led to increased NF-κB –dependent proinflammatory cytokine transcription. Functional experiments in the HA20 patients’ immune cells uncovered a novel caspase-8-dependent mechanism of NLRP3 inflammasome hyperresponsiveness that mediated the excessive secretion of interleukin-1β and -18.ConclusionsThe current findings significantly deepen our understanding of the molecular mechanisms underlying HA20 and other diseases associated with reduced A20 expression or function, paving the way for future therapeutic targeting of the pathway.

scholarly journals Cultural dermatoses: A review

2021 ◽  
Vol 0 ◽  
pp. 1-7
Author(s):  
Reshma Kunhi Kannan
Keyword(s):  
Child Abuse ◽  
Contact Dermatitis ◽  
Allergic Contact Dermatitis ◽  
Correct Diagnosis ◽  
Religious Practices ◽  
Cultural Perception ◽  
Acupuncture And Moxibustion ◽  
And Migration ◽  
Allergic Contact ◽  
The Impact

The impact of globalization and migration is reflected in cultural dermatoses which in earlier times were localized to specific regions. Therapeutic, cosmetic, and religious practices can lead to dermatoses. Therapeutic practices such as cupping, coining, acupuncture, and moxibustion may cause purpura and ecchymoses which are sometimes mistaken for child abuse. Cultural perception of beauty is often the motivation behind practices such as threading, use of bleaching agents, henna, bindi, and hair oils, which, in turn, can cause irritant and allergic contact dermatitis as well as a host of other dermatoses. Prayer nodules and turban dermatoses may manifest as outcomes of culture specific religious practices. A knowledge of these conditions can help the dermatologist to offer a correct diagnosis and treatment.

scholarly journals Haploinsufficiency of A20 impairs protein–protein interactome and leads into caspase-8-dependent enhancement of NLRP3 inflammasome activation

RMD Open ◽  
2018 ◽  
Vol 4 (2) ◽  
pp. e000740 ◽  
Author(s):  
Kristiina Rajamäki ◽  
Salla Keskitalo ◽  
Mikko Seppänen ◽  
Outi Kuismin ◽  
Paula Vähäsalo ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Immune Cells ◽  
Nlrp3 Inflammasome ◽  
Molecular Mechanisms ◽  
Luciferase Reporter ◽  
Caspase 8 ◽  
Inflammasome Activation ◽  
Loss Of Function ◽  
Pyrin Domain ◽  
Protein Interactome

ObjectivesTNFAIP3 encodes A20 that negatively regulates nuclear factor kappa light chain enhancer of activated B cells (NF-κB), the major transcription factor coordinating inflammatory gene expression. TNFAIP3 polymorphisms have been linked with a spectrum of inflammatory and autoimmune diseases and, recently, loss-of-function mutations in A20 were found to cause a novel inflammatory disease ‘haploinsufficiency of A20’ (HA20). Here we describe a family with HA20 caused by a novel TNFAIP3 loss-of-function mutation and elucidate the upstream molecular mechanisms linking HA20 to dysregulation of NF-κB and the related inflammasome pathway.MethodsNF-κB activation was studied in a mutation-expressing cell line using luciferase reporter assay. Physical and close-proximity protein–protein interactions of wild-type and TNFAIP3 p.(Lys91*) mutant A20 were analysed using mass spectrometry. NF-κB -dependent transcription, cytokine secretion and inflammasome activation were compared in immune cells of the HA20 patients and control subjects.ResultsThe protein–protein interactome of p.(Lys91*) mutant A20 was severely impaired, including interactions with proteins regulating NF-κB activation, DNA repair responses and the NLR family pyrin domain containing 3 (NLRP3) inflammasome. The p.(Lys91*) mutant A20 failed to suppress NF-κB signalling, which led to increased NF-κB -dependent proinflammatory cytokine transcription. Functional experiments in the HA20 patients’ immune cells uncovered a novel caspase-8-dependent mechanism of NLRP3 inflammasome hyperresponsiveness that mediated the excessive secretion of interleukin-1β and interleukin-18.ConclusionsThe current findings significantly deepen our understanding of the molecular mechanisms underlying HA20 and other diseases associated with reduced A20 expression or function, paving the way for future therapeutic targeting of the pathway.

scholarly journals Pterostilbene Attenuates Hexavalent Chromium-Induced Allergic Contact Dermatitis by Preventing Cell Apoptosis and Inhibiting IL-1β-Related NLRP3 Inflammasome Activation

2018 ◽  
Vol 7 (12) ◽  
pp. 489 ◽  
Author(s):  
Bour-Jr Wang ◽  
Hui-Wen Chiu ◽  
Yong-Lin Lee ◽  
Chia-Yi Li ◽  
Ying-Jan Wang ◽  
...  
Keyword(s):  
Contact Dermatitis ◽  
Protein Kinase ◽  
Allergic Contact Dermatitis ◽  
Hexavalent Chromium ◽  
Nlrp3 Inflammasome ◽  
Hacat Cells ◽  
Skin Reactions ◽  
Tnf Α ◽  
Allergic Contact

Hexavalent chromium (Cr(VI)) is widely used in many industries but can induce contact dermatitis especially in cement industries. Many cement workers suffer from Cr(VI)-induced allergic contact dermatitis (ACD), and prevention and therapeutic strategies are still lacking. Pterostilbene (PT) is a natural compound predominantly found in blueberries. Studies indicate the potential use of PT as an effective anti-oxidative and anti-inflammatory agent. Herein, we investigated the possible mechanisms involved and whether chromium-induced ACD could be effectively inhibited by treating PT. In our in vivo study, epidermal Cr(VI) administration causes cutaneous inflammation in mice ear skin, and the pro-inflammatory cytokines, TNF-α and IL-1β, were found in the epidermis, presenting the level of increase after Cr(VI) treatment. Meanwhile, the results of our in vitro experiment showed that apoptosis and endoplasmic reticulum (ER) stress were induced after treatment with different concentrations of Cr(VI) in HaCaT cells (human keratinocyte). Cr(VI) also induced TNF-α and IL-1β mRNA expressions, through the activation of the p38 mitogen-activated protein kinase (MAPK)/MAPK-activated protein kinase 2 (MK2) pathway. Notably, the severity of the skin reactions in the epicutaneous elicitation test significantly diminished when the mouse was treated with PT. Likewise, PT intervention also ameliorated the inflammation and apoptosis of HaCaT cells in vitro. Furthermore, our current findings demonstrated that the NLRP3 inflammasome could be involved in the Cr(VI)-mediated inflammation and apoptosis of ACD. Thus, interrupting this mechanism with proper nontoxic agents, such as PT, could be a new option to improve occupational chromium toxicity and hypersensitivity.

scholarly journals ER Stress Activates the NLRP3 Inflammasome: A Novel Mechanism of Atherosclerosis

2019 ◽  
Vol 2019 ◽  
pp. 1-18 ◽  
Author(s):  
Xinnong Chen ◽  
Xiaochen Guo ◽  
Qihui Ge ◽  
Yixuan Zhao ◽  
Huaiyu Mu ◽  
...  
Keyword(s):  
Er Stress ◽  
Nlrp3 Inflammasome ◽  
Molecular Mechanisms ◽  
Ros Generation ◽  
Macromolecular Complex ◽  
Inflammasome Activation ◽  
Cellular Processes ◽  
Pyrin Domain ◽  
Nlrp3 Inflammasome Activation ◽  
The Unfolded Protein Response

The endoplasmic reticulum (ER) is an important organelle that regulates several fundamental cellular processes, and ER dysfunction has implications for many intracellular events. The nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome is an intracellularly produced macromolecular complex that can trigger pyroptosis and inflammation, and its activation is induced by a variety of signals. ER stress has been found to affect NLRP3 inflammasome activation through multiple effects including the unfolded protein response (UPR), calcium or lipid metabolism, and reactive oxygen species (ROS) generation. Intriguingly, the role of ER stress in inflammasome activation has not attracted a great deal of attention. In addition, increasing evidence highlights that both ER stress and NLRP3 inflammasome activation contribute to atherosclerosis (AS). AS is a common cardiovascular disease with complex pathogenesis, and the precise mechanisms behind its pathogenesis remain to be determined. Both ER stress and the NLRP3 inflammasome have emerged as critical individual contributors of AS, and owing to the multiple associations between these two events, we speculate that they contribute to the mechanisms of pathogenesis in AS. In this review, we aim to summarize the molecular mechanisms of ER stress, NLRP3 inflammasome activation, and the cross talk between these two pathways in AS in the hopes of providing new pharmacological targets for AS treatment.

scholarly journals An update on the regulatory mechanisms of NLRP3 inflammasome activation

2021 ◽  
Author(s):  
Seungwha Paik ◽  
Jin Kyung Kim ◽  
Prashanta Silwal ◽  
Chihiro Sasakawa ◽  
Eun-Kyeong Jo
Keyword(s):  
Protein Interactions ◽  
Posttranslational Modifications ◽  
Nlrp3 Inflammasome ◽  
Molecular Mechanisms ◽  
Inflammasome Activation ◽  
Protein Protein Interactions ◽  
Regulatory Pathways ◽  
Pyrin Domain ◽  
Spatiotemporal Regulation ◽  
Nlrp3 Inflammasome Activation

AbstractThe NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome is a multiprotein complex involved in the release of mature interleukin-1β and triggering of pyroptosis, which is of paramount importance in a variety of physiological and pathological conditions. Over the past decade, considerable advances have been made in elucidating the molecular mechanisms underlying the priming/licensing (Signal 1) and assembly (Signal 2) involved in NLRP3 inflammasome activation. Recently, a number of studies have indicated that the priming/licensing step is regulated by complicated mechanisms at both the transcriptional and posttranslational levels. In this review, we discuss the current understanding of the mechanistic details of NLRP3 inflammasome activation with a particular emphasis on protein-protein interactions, posttranslational modifications, and spatiotemporal regulation of the NLRP3 inflammasome machinery. We also present a detailed summary of multiple positive and/or negative regulatory pathways providing upstream signals that culminate in NLRP3 inflammasome complex assembly. A better understanding of the molecular mechanisms underlying NLRP3 inflammasome activation will provide opportunities for the development of methods for the prevention and treatment of NLRP3 inflammasome-related diseases.

scholarly journals Application of proteomics in the elucidation of chemical-mediated allergic contact dermatitis

2017 ◽  
Vol 6 (5) ◽  
pp. 595-610 ◽  
Author(s):  
Tessa Höper ◽  
Franz Mussotter ◽  
Andrea Haase ◽  
Andreas Luch ◽  
Tewes Tralau
Keyword(s):  
Contact Dermatitis ◽  
Hypersensitivity Reaction ◽  
Allergic Contact Dermatitis ◽  
Molecular Mechanisms ◽  
Allergic Contact

Allergic contact dermatitis (ACD) is a widespread hypersensitivity reaction of the skin. While technically still challenging in the context of ACD, proteomics provide a powerful and useful tool to study the underlying molecular mechanisms as well as for the identification of biomarkers.

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