Sensing platforms of the innate immune system are critical for orchestrating the communitcation between the human body and its microbial environment. We are studying the integrative activity of multiple platforms at mucosal surfaces - the place of intimate contact between the host and the world surrounding it.
The balance between activation of the innate immune system and microbial colonization on mucosal surfaces is essential for health, as distortions in the balance can lead to the development of a multitude of diseases - ranging from chronic inflammatory disease to autoimmunity, obesity, and cancer. We are striving to decipher the mechanisms regulating the communitcation between the innate immune system, our microbial environment, and their effects on a variety of human diseases.
Inflammation is associated with transient loss of tissue function and in some cases loss of tissue structure and integrity. This is especially delicate at the intestinal mucosal surface, the barrier between the eukaryotic and prokaryotic parts of the mammalian "super-organism". We are studying how the elicitation of inflammation is regulated at mucosal surfaces, i.e. the mechanisms which regulate the switch from homeostasis to inflammation at this peculiar barrier between the inside and outside.
Dysfunctions in these mechanisms result in the development of chronic inflammation. In the intestine, chronic inflammation leads to the development of inflammatory bowel disease (IBD), such as Crohn's disease and ulcerative colitis. We are interesting in deciphering the cross-regulation of inflammation, tolerance, and the microbial ecosystem at mucosal interfaces, and how aberrations in this process manifest in IBD development.
In particular, we are interested in the inflammasome, a protein complex of the innate immune system, which functions as a sensor of both microbial products and host-derived damage signals. Upon activation, NLR sensor proteins, adaptor proteins (ASC) and inflammatory caspases assemble to form the inflammasome. Activation of the inflammasome leads to the catalytic processing of the cytokines IL-1 and IL-18, as well as to a peculiar form of cell death called pyroptosis.
We have identified the NLRP6 inflammasome as a novel critical regulator of host-microbial mutualism in the intestine. NLRP6 signaling in intestinal epithelial cells is required for maintaining a stable microbial composition in the intestine, and aberrations in this system lead to the outgrowth of bacterial species which are normally suppressed.