Immune Functions of Myeloid Syk-coupled C-type Lectin Receptors Sensing Necrosis

Ziel

Necrosis triggers an inflammatory response driven by macrophages that normally contributes to tissue repair but, under certain conditions, can induce a state of chronic inflammation that forms the basis of many diseases. In addition, dendritic cell (DC)-mediated presentation of antigens from necrotic cells can trigger adaptive immunity in infection-free situations, such as autoimmunity or therapy-induced tumour rejection. Recently, we and others have identified the myeloid C-type lectin receptors (CLRs) CLEC9A (DNGR-1), in DC, and Mincle, in macrophages, as receptors for necrotic cells that can signal via the Syk kinase. Previous studies on similar Syk-coupled CLRs showed that Dectin-1 and Dectin-2 can induce innate and adaptive immune responses. We thus hypothesise that recognition of cell death by myeloid Syk-coupled CLRs is at the root of immune pathologies associated with accumulation of dead cells. The overall objective of this proposal is to investigate necrosis sensing by myeloid cells as a trigger of immunity and to study the underlying molecular mechanisms. Our first goal is to characterise signalling and gene induction via CLEC9A as a model necrosis receptor in DCs. Second, we will investigate the role of myeloid Syk-coupled necrosis-sensing CLRs in animal models of atherosclerosis, lupus and immunity to chemotherapy-treated tumours. Our preliminary data suggest that additional receptors can couple necrosis recognition to the Syk pathway in DC; thus, our third aim is to identify novel myeloid Syk-coupled receptors for necrotic cells. Characterisation of the outcomes of sensing necrosis by myeloid Syk-coupled receptors and their effect on the proposed pathologies promises to identify new mechanisms and targets for the treatment of these diseases.

Wissenschaftliches Gebiet

Finanzierungsplan

ERC-SG - ERC Starting Grant

Gastgebende Einrichtung

CENTRO NACIONAL DE INVESTIGACIONES CARDIOVASCULARES CARLOS III (F.S.P.)

EU-Beitrag

€ 1 297 671,00

Adresse

CALLE MELCHOR FERNANDEZ ALMAGRO 3
28029 Madrid
Spanien

Region

Comunidad de Madrid Comunidad de Madrid Madrid

Aktivitätstyp

Research Organisations

Hauptforscher

David Sancho Madrid (Dr.)

Kontakt Verwaltung

Inga Dreville (Ms.)

Links

Die Organisation kontaktieren Website

Gesamtkosten

Keine Daten

Begünstigte (1)