Innate immunity ; Inflammation; Cellular Homeostasis; Inflammasome; Unfolded Protein Response
Spel Lotte, Martinon Fabio (2020), Inflammasomes contributing to inflammation in arthritis, in Immunological Reviews
Jamilloux Yvan, Lagrange Brice, Di Micco Antonia, Bourdonnay Emilie, Provost Angélina, Tallant Rémy, Henry Thomas, Martinon Fabio (2018), A proximity-dependent biotinylation (BioID) approach flags the p62/sequestosome-1 protein as a caspase-1 substrate, in Journal of Biological Chemistry
, 293(32), 12563-12575.
Martinon Fabio (2018), Inflammation initiated by stressed organelles, in Joint Bone Spine
, 85(4), 423-428.
Lugrin Jérôme, Martinon Fabio (2018), The AIM2 inflammasome: Sensor of pathogens and cellular perturbations, in Immunological Reviews
, 281(1), 99-114.
So Alexander K., Martinon Fabio (2017), Inflammation in gout: mechanisms and therapeutic targets, in Nature Reviews Rheumatology
, 13(11), 639-647.
Inflammation contributes to innate immune responses and is triggered by the presence of non-self patterns characteristic of infectious agents, or danger signals released from damaged tissues. A growing number of evidences also indicate that transient and non-lethal alterations of cellular homeostasis can promote low-grade inflammation. However the nature and outcome of these responses are poorly understood. We recently identified a cellular perturbation that share features with the endoplasmic reticulum (ER) stress but is characterized by transient defects in the nuclear envelope. We found that this nuclear envelope (NE) stress is associated with the exposure of self-DNA that is then detected by cGAS and the AIM2 inflammasome to promote inflammation. These findings support the model that loss of cellular compartmentalization is inflammatory and highlight the role of mammalian innate immune sensors as guardians of cellular integrity.The goals of this proposal are to elucidate the molecular mechanisms and pathways that can lead to cellular perturbations including nuclear envelop stress, to define the resulting inflammatory pathways engaged and to address the physiological relevance of the resulting autoinflammation in health and diseases. Three complementary research sub-projects were designed to provide a comprehensive study of the NE-stress and related perturbation of cellular homeostasis and to address the physiological role of these responses. The first sub-project will identify relevant signals and mechanisms that promote NE-stress. The second sub-project is aimed at deciphering the inflammatory pathways triggered by alteration of NE homeostasis. The third sub-project focuses on diseases and conditions characterized by NE alterations and the contribution of inflammasomes and related immune pathways to inflammation in these pathologies.This project will pioneer the field of NE-stress in immunity, it will identify important mechanisms and pathways involved in the NE-stress response and will provide new insights on the role of autoinflammation in diseases and conditions characterized by loss of NE homeostasis, including autoinflammatory diseases, laminopathies, and cancer.