Elucidating the cell type specific molecular mechanisms of NLRC4 inflammasome activation

01 October 2020 → 31 December 2021
Regional and community funding: Special Research Fund
Research disciplines
  • Medical and health sciences
    • Inflammation
    • Cell signalling
Innate immune response bacterial infection autoinflammatory disease inflammasome
Project description

The NLRC4 inflammasome is a protein complex that recognizes
intracellular bacterial flagellin and as such protects against enteric
pathogens such as Salmonella. However, hyper-activation of the
NLRC4 inflammasome due to mutations in the Nlrc4 gene has been
suggested to cause autoinflammatory diseases (AID). Because the
molecular mechanisms underlying hyper-activation of the NLRC4
inflammasome remain to be elucidated we generated a mouse line
that genetically resemble NLRC4-associated AID. We found that the
molecular mechanisms responsible for NLRC4 hyper-activation and
subsequent auto-inflammation in these mice reside specifically in
intestinal epithelial cells and not in macrophages. In this project, I will
identify novel components of the NLRC4 inflammasome complex and
validate their involvement in AID and in Salmonella-induced NLRC4
activation in order to reveal the unique mechanisms by which NLRC4
-initiated pro-inflammatory responses are regulated in an intestinal
epithelial cell specific manner. Pinpointing molecular mechanisms of
NLRC4 activation will be relevant to NLRC4-AID, and might also
reveal novel insights into host innate immune responses to infections
with flagellated bacteria.