INFLAMMACT · Role of caspase-11 in inflammasome signaling and the innate immune response
7РП — „Хора“ (Действия „Мария Кюри“)
- Период
- 2010-05-01 → 2013-04-30
- Финансиране от ЕС
- 75 000 €
- Участници
- 1
- Схема
- MC-IRG
Линиите свързват координатора с партньорите.
Накратко на български
Ролята на протеина caspase-11 се изследва при отговора на имунната система към бактерии като E. coli. Разбирането на този механизъм помага да се разбере как тялото се бори с инфекциите и автоимунните заболявания.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Role of caspase-11 in inflammasome signaling and the innate immune response
Microbial infections and autoimmune diseases continue to threaten human health worldwide. Orchestration of an appropriate host defence responses against bacterial and viral infections is accomplished in part through the production of potent inflammatory cytokines. In particular, the related cytokines interleukin (IL)-1beta and IL-18 were recognized early on for their ability to cause a wide variety of biological effects associated with infection, inflammation and autoimmune processes. These cytokines are matured in large protein complexes termed inflammasomes through proteolytic maturation by the cystein protease caspase-1. Unlike caspase-1, the roles of the closely related cystein protease caspase-11 in cytokine maturation remain unclear. In this project, we addressed this issue by monitoring cytokine defects in caspase-11 deficient mice and cells in mouse and cellular models of infection and inflammation. In aim 1 of the project, we set up a colony of caspase-11-deficient mice in our facility, macrophages of which are used to study the role of caspase-11 in inflammasome activation and IL-1beta secretion. We found that caspase-11 is dispensable for inflammasome activation and cytokine secretion from LPS-activated macrophages exposed to canonical inflammasome triggers such as ATP, Salmonella and dsDNA. However, caspase-11 was required for inflammasome activation and IL-1beta secretion in response to enterobacteria such as E. coli and C. rodentium. Caspase-11 was also required for IL-1beta secretion during LPS-induced endotoxemia in vivo. In aim 2 of the project, we determined the proteome-wide digestome of caspase-11. Putative caspase-11 substrates identified by this analysis have been validated in in vitro setups with recombinantly purified caspase-11, in overexpression systems and a subset was confirmed in cellular and in vivo models of inflammation and infection. Ongoing studies are aimed at further validating the role of these caspase-11 substrates in cellular and in vivo models of inflammation and infection. Full elucidation of the role of caspase-11 in inflammasome signaling and the innate immune response will provide new insights into the mechanisms governing immunity and may pave the way for new therapeutic approaches for autoimmune disorders.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
Innate immune cells such as macrophages and dendritic cells produce potent inflammatory cytokines to mount an appropriate immune response against microbial threats. The related cytokines interleukin (IL)-1beta and IL-18 require cleavage by the cysteine protease caspase-1 to generate biologically active IL-1beta and IL-18. Caspase-1 itself is synthesized as zymogen that interacts with certain members of the intracellular NOD-like receptor (NLR) family in infected macrophages to form large protein complexes named ‘inflammasomes’. The importance of inflammasomes is evident from the genetic variations in the NLR proteins Nalp1 and Nalp3 that are associated with autoinflammatory disorders and increased susceptibility to microbial infection. However, the molecular mechanisms of inflammasome activation and the role of caspase-11 have remained unclear. Caspase-11 has been suggested as an upstream and downstream regulator of caspase-1 functions in LPS-stimulated cells. However, its role in specific infammasomes and its contribution to substrate cleavage in innate immunity remain to be explored. We generated caspase-11 knockout mice to characterize the physiological role of caspase-11 in inflammasome signaling and the innate immune response. In Aim 1, we will characterize the role of caspase-11 in activation of the different caspase-1 inflammasomes. In Aim 2, the proteome-wide caspase-11 degradome will be determined using mass spectrometry-based COFRADIC technology. Primary macrophages from caspase-11 knockout mice will be used to validate the caspase-11 degradome under activating conditions. These approaches will generate a wealth of new information regarding the role of caspase-11 in innate immunity. Elucidating the role of caspase-11 in inflammasome signaling and the innate immune response will provide new insights into the mechanisms governing immunity and may pave the way for new therapeutic approaches for autoimmune disorders.
Оригинален текст от CORDIS (на английски).
Участници
- VIB VZW · ZWIJNAARDE - GENTКоординаторБелгия
Връзки
Данни: CORDIS, © Европейски съюз