CD95 recruits PLCγ1 to trigger a calcium response promoting Th17 accumulation in inflamed organs of lupus mice

CD95 ligand (CD95L) is expressed by immune cells and triggers apoptotic death. Metalloprotease-cleaved CD95L (cl-CD95L) is released into the bloodstream but does not trigger apoptotic signaling. Hence, the pathophysiological role of cl-CD95L remains unclear. We observed that skin-derived endothelial cells from systemic lupus erythematosus (SLE) patients expressed CD95L, and that after cleavage, cl-CD95L promoted T helper 17 (Th17) lymphocyte transmigration across the endothelial barrier at the expense of T regulatory cells. T cell migration relied on a direct interaction between the CD95 domain called calcium-inducing domain (CID) and the Src homology 3 domain of phospholipase Cγ1. Th17 cells stimulated with cl-CD95L produced sphingosine-1-phosphate (S1P), which promoted endothelial transmigration by activating the S1P receptor 3. We generated a cell-penetrating CID peptide that prevented Th17 cell transmigration and alleviated clinical symptoms in lupus mice. Therefore, neutralizing the CD95 non-apoptotic signaling pathway may be attractive therapeutic approach for SLE treatment

CD95-mediated calcium signaling promotes T helper 17 trafficking to inflamed organs in lupus-prone mice

CD95 ligand (CD95L) is expressed by immune cells and triggers apoptotic death. Metalloprotease-cleaved CD95L (cl-CD95L) is released into the bloodstream but does not trigger apoptotic signaling. Hence, the pathophysiological role of cl-CD95L remains unclear. We observed that skin-derived endothelial cells from systemic lupus erythematosus (SLE) patients expressed CD95L and that after cleavage, cl-CD95L promoted T helper 17 (Th17) lymphocyte transmigration across the endothelial barrier at the expense of T regulatory cells. T cell migration relied on a direct interaction between the CD95 domain called calcium-inducing domain (CID) and the Src homology 3 domain of phospholipase Cγ1. Th17 cells stimulated with cl-CD95L produced sphingosine-1-phosphate (S1P), which promoted endothelial transmigration by activating the S1P receptor 3. We generated a cell-penetrating CID peptide that prevented Th17 cell transmigration and alleviated clinical symptoms in lupus mice. Therefore, neutralizing the CD95 non-apoptotic signaling pathway could be an attractive therapeutic approach for SLE treatment

A participação intitutionalizada em espaços protegidos habitados. Quais são as contribuições à eco-atorização dos participantes e ao desenvolvimento territorial ?Olhares cruzados para 6 iniciativas de desenvolvimento do parque Natural Regional Scarpe-Escaut (França) e do Mosaico Sertão Veredas-Peruaçu (Brasil).

Managers of Inhabited Protected Areas (IPA) promote participatory development initiatives in order to protect natural and cultural heritages. This research investigates if the institutionalized participation favors the transformation of the participants into eco-actors authors of bottom-up initiatives ("eco-actorisation"), and supports the territorial development. Our qualitative survey focused on a cross-sectional analysis of six cases of local development initiatives from two IPAs. It seeks to highlight some favorable outcomes and to stir some debates. The participation of both local stakeholders and inhabitants in the creation and the management of these IPAs is unanimously encouraged by the international framework, the public policies and the IPAs managers themselves. Implementation reveals very contrasting and imperfect situations. Whether in terms of community and institutional engagement, participatory tools and methods or power dynamics: progress remains to be made. Yet, these initiatives - which would probably notexist without these institutional incentives - attempt to activate and specify natural and / or culturalresources. Eco-actorization is rarely "accomplished" but often partially observed. While six theseinitiatives do not exactly correspond to the concept of territorial development, they nonethelesscontribute to creating a favorable “soil” for this development process, and a certain "better-being"for stakeholders involved. One of the scenarios to be considered would be to transform the EPHinto eco-actors incubators, and their managers into partners of bottom-up initiatives.Les gestionnaires des espaces protégés habités (EPH) impulsent des initiatives participatives de développement soucieuses de protéger les patrimoines naturels et culturels. Cette recherche vérifie si la participation institutionnalisée favorise la transformation des participants en éco-acteurs, auteurs d’initiatives ascendantes (l’éco-acteurisation), et alimente le développement territorial. Notre enquête qualitative a porté sur une analyse croisée de six initiatives de développement local issues de deux EPH. Elle met en évidence leurs fonctionnements et alimente quelques débats. La participation des acteurs locaux et habitants à la création et gestion de ces EPH est unanimement encouragée par le cadre international, les politiques publiques et les gestionnaires des EPH. La mise en oeuvre révèle des situations très contrastées et imparfaites. Des marges de progrès subsistent, que ce soit au niveau de la quantité, diversité ou représentativité des acteurs concernés, de l’animation des dispositifs participatifs ou encore de la répartition des pouvoirs. Néanmoins ces initiatives - qui n’existeraient probablement pas sans ces incitations institutionnelles - tentent d’activer et de spécifier des ressources naturelles et/ou culturelles. L’éco-acteurisation est rarement « accomplie » mais souvent partiellement observée. Si ces initiatives ne correspondent pas exactement au concept de développement territorial, elles contribuent à créer un terreau favorable à ce processus de développement, et engendrent un certain mieux-être pour les acteurs concernés.Un des scénarios à envisager serait de transformer les EPH en des incubateurs à éco-acteurs, et leurs gestionnaires en des partenaires d’initiatives ascendantes.Gestores de espaços protegidos habitados (EPH) impulsionam iniciativas participativas de desenvolvimento ambicionando a proteção dos patrimônios naturais e culturais. Esta pesquisa verifica se a participação institucionalizada promove a transformação dos participantes em ecoatores, autores de iniciativas ascendentes (a "eco-atorização") e alimenta o desenvolvimento territorial. Nossa investigação qualitativa abrangeu uma análise cruzada de seis iniciativas de desenvolvimento local em dois EPH. Ela destaca os seus funcionamentos e alimenta alguns debates. A participação dos atores locais e moradores na criação e gestão de EPH é incentivada porunanimidade pelo quadro internacional, as políticas públicas e os gestores de EPH. A implementação revela situações muito contrastantes e imperfeitas. Melhorias precisam ser feitas, seja em termos de quantidade, diversidade e representatividade dos atores implicados, de animação dos dispositivos participativos ou da divisão de poderes. No entanto, essas iniciativas - que provavelmente não existiriam sem tais incentivos institucionais - tentam ativar e especificar recursos naturais e / ou culturais. A eco-atorização é raramente "cumprida", mas muitas vezes parcialmente observada. Se essas iniciativas não correspondem exatamente ao conceito dedesenvolvimento territorial, elas ajudam a criar um “terreno” favorável a esse processo de desenvolvimento e geram para as partes interessadas um certo "melhor-estar". Um cenário a considerar seria o de transformação dos EPH em incubadoras à eco-atores, e quanto aos gerentes torná-los parceiros das iniciativas ascendentes

La participation institutionnalisée dans les espaces protegés habités. Quelles contributions à leco-acteurisation des participants et audeveloppement territorial?: regards croisés sur 6 initiatives de développement du Parc naturel régional Scarpe-Escaut (France) et de la Mosaïque daires protégées Sertão Veredas-Peruaçu (Brésil)

Exportado OPUSMade available in DSpace on 2019-08-14T20:22:38Z (GMT). No. of bitstreams: 1 tese_lucie_morere_2017.pdf: 69153725 bytes, checksum: 5f5ad6854ae744f59dfa7c8ae4b1fcfa (MD5) Previous issue date: 10Gestores de espaços protegidos habitados (EPH) impulsionam iniciativas participativas de desenvolvimento ambicionando a proteção dos patrimônios naturais e culturais. Esta pesquisa verifica se a participação institucionalizada promove a transformação dos participantes em ecoatores, autores de iniciativas ascendentes (a "eco-atorização") e alimenta o desenvolvimento territorial. Nossa investigação qualitativa abrangeu uma análise cruzada de seis iniciativas de desenvolvimento local em dois EPH. Ela destaca os seus funcionamentos e alimenta alguns debates. A participação dos atores locais e moradores na criação e gestão de EPH é incentivada por unanimidade pelo quadro internacional, as políticas públicas e os gestores de EPH. A implementação revela situações muito contrastantes e imperfeitas. Melhorias precisam ser feitas, seja em termos de quantidade, diversidade e representatividade dos atores implicados, de animação dos dispositivos participativos ou da divisão de poderes. No entanto, essas iniciativas - que provavelmente não existiriam sem tais incentivos institucionais - tentam ativar e especificar recursos naturais e / ou culturais. A eco-atorização é raramente "cumprida", mas muitas vezes parcialmente observada. Se essas iniciativas não correspondem exatamente ao conceito de desenvolvimento territorial, elas ajudam a criar um terreno favorável a esse processo de desenvolvimento e geram para as partes interessadas um certo "melhor-estar". Um cenário a considerar seria o de transformação dos EPH em incubadoras à eco-atores, e quanto aos gerentes torná-los parceiros das iniciativas ascendentes.Managers of Inhabited Protected Areas (IPA) promote participatory development initiatives in order to protect natural and cultural heritages. This research investigates if the institutionalized participation favors the transformation of the participants into eco-actors authors of bottom-up initiatives ("eco-actorisation"), and supports the territorial development. Our qualitative survey focused on a cross-sectional analysis of six cases of local development initiatives from two IPAs. It seeks to highlight some favorable outcomes and to stir some debates. The participation of both local stakeholders and inhabitants in the creation and the management of these IPAs is unanimously encouraged by the international framework, the public policies and the IPAs managers themselves. Implementation reveals very contrasting and imperfect situations. Whether in terms of community and institutional engagement, participatory tools and methods or power dynamics: progress remains to be made. Yet, these initiatives - which would probably not exist without these institutional incentives - attempt to activate and specify natural and / or cultural resources. Eco-actorization is rarely "accomplished" but often partially observed. While six these initiatives do not exactly correspond to the concept of territorial development, they nonetheless contribute to creating a favorable soil for this development process, and a certain "better-being" for stakeholders involved. One of the scenarios to be considered would be to transform the EPH into eco-actors incubators, and their managers into partners of bottom-up initiatives

HIV Protease Inhibitors Cure Lupus-Prone Mice and Prevent T Helper 17 Cell-Driven Inflammation By Inhibiting CD95-Non-Apoptotic Signaling Pathway

International audienc

CD95 recruits PLCγ1 to trigger a calcium response promoting Th17 accumulation in inflamed organs of lupus mice

CD95 ligand (CD95L) is expressed by immune cells and triggers apoptotic death. Metalloprotease-cleaved CD95L (cl-CD95L) is released into the bloodstream but does not trigger apoptotic signaling. Hence, the pathophysiological role of cl-CD95L remains unclear. We observed that skin-derived endothelial cells from systemic lupus erythematosus (SLE) patients expressed CD95L, and that after cleavage, cl-CD95L promoted T helper 17 (Th17) lymphocyte transmigration across the endothelial barrier at the expense of T regulatory cells. T cell migration relied on a direct interaction between the CD95 domain called calcium-inducing domain (CID) and the Src homology 3 domain of phospholipase Cγ1. Th17 cells stimulated with cl-CD95L produced sphingosine-1-phosphate (S1P), which promoted endothelial transmigration by activating the S1P receptor 3. We generated a cell-penetrating CID peptide that prevented Th17 cell transmigration and alleviated clinical symptoms in lupus mice. Therefore, neutralizing the CD95 non-apoptotic signaling pathway may be attractive therapeutic approach for SLE treatment

Disrupting the CD95-PLC gamma 1 interaction prevents Th17-driven inflammation

International audienceCD95L is a transmembrane ligand (m-CD95L) that is cleaved by metalloproteases to release a soluble ligand (s-CD95L). Unlike m-CD95L, interaction between s-CD95L and CD95 fails to recruit caspase-8 and FADD to trigger apoptosis and instead induces a Ca2+ response via docking of PLC gamma 1 to the calcium-inducing domain (CID) within CD95. This signaling pathway induces accumulation of inflammatory Th17 cells in damaged organs of lupus patients, thereby aggravating disease pathology. A large-scale screen revealed that the HIV protease inhibitor ritonavir is a potent disruptor of the CD95-PLC gamma 1 interaction. A structure-activity relationship approach highlighted that ritonavir is a peptidomimetic that shares structural characteristics with CID with respect to docking to PLC gamma 1. Thus, we synthesized CID peptidomimetics abrogating both the CD95-driven Ca2+ response and transmigration of Th17 cells. Injection of ritonavir and the CID peptidomimetic into lupus mice alleviated clinical symptoms, opening a new avenue for the generation of drugs for lupus patients