55 research outputs found
Photoaging and skin cancer: Is the inflammasome the missing link?
Photoaging and epithelial skin tumorigenesis are complex processes triggered mainly by UV radiation from
chronic sun exposure. This leads to DNA damage and reactive oxygen species (ROS) production, which initiate
an inflammatory response that alters cell structure and function.
Changes in cell homeostasis and ROS production activate intracellular multiprotein platforms called inflammasomes.
Inflammasomes nucleate around cytoplasmic receptors mainly of the NLR (nucleotide-binding
domain and leucine-rich repeat) family and regulate caspase-1-dependant secretion of pro-inflammatory interleukin
(IL)1ÎČ and IL18 cytokines, and an inflammatory form of death named pyroptosis.
NLRP1 inflammasomes have taken centre stage in skin biology, as mutations in NLRP1 underlie the genetic
etiology of dermatological diseases and increase the susceptibility to skin cancer. Targeting inflammasome(s)
might be an important approach to improve skin inflammation, photoaging and reduce the risk of epithelial skin
tumorigenesis. In this context, we discuss the potential implication of NLRP1 and NLRP3 inflammasomes
Inflammasome biology, molecular pathology and therapeutic implications
Inflammasomes are intracellular multiprotein signaling complexes, mainly present in myeloid cells. They
commonly assemble around a cytoplasmic receptor of the nucleotide-binding leucine-rich repeat containing
receptor (NLR) family, although other cytoplasmic receptors like pyrin have been shown to forminflammasomes.
The nucleation of the multiprotein scaffolding platform occurs upon detection of a microbial, a danger
or a homeostasis pattern by the receptor that will, most commonly, associate with the adaptor protein ASC
(apoptosis-associated speck-like protein containing a CARD) through homotypic domain interactions resulting
in recruitment of procaspase-1. This will lead to the autoproteolytic activation of caspase-1, which regulates
the secretion of proinflammatory IL1ÎČ and IL18 cytokines and pyroptosis, a caspase-1-mediated form of
cell death. Pyroptosis occurs through cleavage of Gasdermin D, a membrane pore forming protein. Recently,
non-canonical inflammasomes have been described, which directly sense intracellular pathogens through
caspase-4 and -5 in humans, leading to pyroptosis.
Inflammasomes are important in host defense; however, a deregulated activity is associated with a number of
inflammatory, immune and metabolic disorders. Furthermore, mutations in inflammasome receptor coding
genes are causal for an increasing number of rare autoinflammatory diseases. Biotherapies targeting the products
of inflammasome activation aswell as molecules that directly or indirectly inhibit inflammasome nucleation and
activation are promising therapeutic areas. This review discusses recent advances in inflammasome biology, the
molecular pathology of several inflammasomes, and current therapeutic approaches in autoinflammatory
diseases and in selected common multifactorial inflammasome-mediated disorders
Physiopathologie des maladies auto-inflammatoires dâexpression cutanĂ©e : Aspects molĂ©culaires et cellulaires
-Les maladies auto-inflammatoires (MAIs) monogĂ©niques sont des maladies rares qui se caractĂ©risent par des accĂšs fĂ©briles rĂ©currents spontanĂ©ment rĂ©solutifs accompagnĂ©s dâune inflammation systĂ©mique. Lâobjectif de ce travail Ă©tait dâidentifier de nouveaux marqueurs diagnostiques de MAIs et dâapprofondir les connaissances physiopathologiques de ces maladies.Le premier volet concernait lâĂ©tude des mutations germinales et somatiques en mosaĂŻque de NLRP3, gĂšne dĂ©jĂ impliquĂ© dans les MAIs. Une rĂ©interprĂ©tation de toutes les mutations rapportĂ©es de NLRP3 chez des patients prĂ©sentant une MAI ainsi quâune Ă©tude approfondie de cinq nouveaux patients, ont permis de caractĂ©riser les spĂ©cificitĂ©s des mutations en mosaĂŻques par rapport aux mutations germinales et de prĂ©ciser le cadre phĂ©notypique de ce syndrome. Le second volet concernait lâidentification dâun nouveau gĂšne de MAI dâexpression cutanĂ©e. Une Ă©tude gĂ©nĂ©tique a Ă©tĂ© rĂ©alisĂ©e au sein dâune grande famille comprenant plusieurs sujets atteints dâurticaire chronique et a permis dâidentifier un nouveau gĂšne de MAI. Des tests fonctionnels ont permis de mettre en Ă©vidence une distribution anormale de la protĂ©ine mutĂ©e au niveau du cytoplasme de la cellule par rapport Ă la protĂ©ine sauvage. Une Ă©tude par protĂ©omique a permis dâidentifier plusieurs partenaires protĂ©iques dont certains sont impliquĂ©s dans lâimmunitĂ© innĂ©e.Au total, ce travail a permis une meilleure connaissance de la physiopathologie des MAIs dâexpression cutanĂ©e avec la caractĂ©risation de mutations en mosaĂŻque dâun gĂšne dĂ©jĂ impliquĂ©, et lâidentification dâun nouveau gĂšne de MAI, marqueur diagnostique particuliĂšrement utile dans ce groupe dâaffection
Pathophysiology of auto-inflammatory diseases with skin manifestations : cellular and molecular approaches
Les maladies auto-inflammatoires (MAIs) monogĂ©niques sont des maladies rares qui se caractĂ©risent par des accĂšs fĂ©briles rĂ©currents spontanĂ©ment rĂ©solutifs accompagnĂ©s dâune inflammation systĂ©mique. Lâobjectif de ce travail Ă©tait dâidentifier de nouveaux marqueurs diagnostiques de MAIs et dâapprofondir les connaissances physiopathologiques de ces maladies. Le premier volet concernait lâĂ©tude des mutations germinales et somatiques en mosaĂŻque de NLRP3, gĂšne dĂ©jĂ impliquĂ© dans les MAIs. Une rĂ©interprĂ©tation de toutes les mutations rapportĂ©es de NLRP3 chez des patients prĂ©sentant une MAI ainsi quâune Ă©tude approfondie de cinq nouveaux patients, ont permis de caractĂ©riser les spĂ©cificitĂ©s des mutations en mosaĂŻques par rapport aux mutations germinales et de prĂ©ciser le cadre phĂ©notypique de ce syndrome. Le second volet concernait lâidentification dâun nouveau gĂšne de MAI dâexpression cutanĂ©e. Une Ă©tude gĂ©nĂ©tique a Ă©tĂ© rĂ©alisĂ©e au sein dâune grande famille comprenant plusieurs sujets atteints dâurticaire chronique et a permis dâidentifier un nouveau gĂšne de MAI. Des tests fonctionnels ont permis de mettre en Ă©vidence une distribution anormale de la protĂ©ine mutĂ©e au niveau du cytoplasme de la cellule par rapport Ă la protĂ©ine sauvage. Une Ă©tude par protĂ©omique a permis dâidentifier plusieurs partenaires protĂ©iques dont certains sont impliquĂ©s dans lâimmunitĂ© innĂ©e. Au total, ce travail a permis une meilleure connaissance de la physiopathologie des MAIs dâexpression cutanĂ©e avec la caractĂ©risation de mutations en mosaĂŻque dâun gĂšne dĂ©jĂ impliquĂ©, et lâidentification dâun nouveau gĂšne de MAI, marqueur diagnostique particuliĂšrement utile dans ce groupe dâaffections.Monogenic auto-inflammatory diseases (AIDs) are rare diseases characterized by recurrent fevers associated with systemic inflammation. The aim of this work was to identify new diagnostic markers of AIDs and to expand the physiopathological knowledge of these diseases. The first part of this work concerned the study of germline and somatic mosaic mutations of NLRP3, a gene already involved in AIDs. A re-assessment of all the reported NLRP3 mutations in AID patients as well as an in-depth study of five new patients allowed characterizing the specificities of mosaic mutations compared to germline mutations. The second part of this work concerned the identification of a new gene of AID. A genetic approach was conducted in a large family comprising several subjects with chronic urticaria and identified a novel AID gene. Functional assays detected abnormal distribution of the mutated protein in the cytoplasm of the cell, relative to the wild-type protein. A proteomic study associated with an immunoprecipitation of the newly identified protein was performed and identified several protein interactors. Among them, some of which are implicated in innate immunity. This work allowed to better understanding the physiopathology AIDs of skin expression, with the characterization of mosaic mutations of a gene already involved, and the identification of a new AID gene, a diagnostic marker particularly useful in this group of affections
PID du nourrisson et de lâenfant : apport de la gĂ©nĂ©tique dans la prise en charge thĂ©rapeutique.
National audienc
Absence of NLRP3 somatic mutations and VEXAS-related UBA1 mutations in a large cohort of patients with Schnitzler syndrome
International audienceNo abstract availabl
Questions about Residual Cell Viability in Cryopreserved Human Amniotic Membrane and Its Impact on Clinical Applications
We questioned the relevance of evaluating residual cell viability in human amniotic membrane (hAM) after its cryopreservation since cell survival is controversial and its ability to act as a matrix (including the presence of growth factors and cytokines) appears to be most important for tissue regeneration purposes. We also discussed the usefulness of osteodifferentiating amniotic cells in whole hAM for bone repair applications. We have evidence that determining residual cell viability after cryopreservation and hAM osteodifferentiation is not justified
Necroptosis study in an epithelial in vitro model expressing surfactant protein A1
International audienc
Photoaging and skin cancer: Is the inflammasome the missing link?
International audiencePhotoaging and epithelial skin tumorigenesis are complex processes triggered mainly by UV radiation from chronic sun exposure. This leads to DNA damage and reactive oxygen species (ROS) production, which initiate an inflammatory response that alters cell structure and function. Changes in cell homeostasis and ROS production activate intracellular multiprotein platforms called inflammasomes. Inflammasomes nucleate around cytoplasmic receptors mainly of the NLR (nucleotide-binding domain and leucine-rich repeat) family and regulate caspase-1-dependant secretion of pro-inflammatory interleukin (IL)1ÎČ and IL18 cytokines, and an inflammatory form of death named pyroptosis. NLRP1 inflammasomes have taken centre stage in skin biology, as mutations in NLRP1 underlie the genetic etiology of dermatological diseases and increase the susceptibility to skin cancer. Targeting inflammasome(s) might be an important approach to improve skin inflammation, photoaging and reduce the risk of epithelial skin tumorigenesis. In this context, we discuss the potential implication of NLRP1 and NLRP3 inflammasome
WT SP-A restores abnormal oligomerization and secretion of mutant SFTPA1 and SFTPA2
International audienc
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