A major research direction in our laboratory is elucidating the mechanisms by which innate immune cells sense danger situations, such as injury, tissue damage or infection with pathogen and the subsequently triggered inflammatory host defense signals that are responsible for eliminating these threats and restoring homeostasis.

 

Inflammation is the central component of this response and is a non-specific immune activation in reaction to any type of tissue injury to support tissue repair. Therefore, acute and well controlled inflammatory reactions are beneficial - however, chronic and inappropriate inflammation is linked to tissue destruction and disease. Therefore, an important goal is to define strategies to limit these excessive and uncontrolled inflammatory reactions.

 

Inflammasomes are protein complexes that link recognition of danger signals to the activation of the inflammatory caspases, including caspase-1 or caspase-4/-5/-11 through canonical and non-canonical pathways, respectively.  The consequence of activation of these caspases is proteolytic maturation and secretion of the pro-inflammatory cytokine substrates IL-1beta and IL-18 and induction of an inflammatory cell death called pyroptosis. In particular, excessive release of IL-1beta is directly linked to the pathology of a wide spectrum of inflammatory diseases.

 

Hence, for developing novel therapies, it is crucial to better understanding inflammasome biology, including the specific function and activation mechanisms of these cytosolic sensors, including the Nod-like receptors (NLRs) and the AIM2-like receptors (ALRs) as well as the molecular mechanisms by which these sensors are regulated - for example by PYD-only proteins (POPs), CARD-only proteins (COPs) and protein modifications.

 

Our research contributed several key aspects of inflammasome biology and the inflammatory response and generated several unique mouse models for inflammasome studies. We discovered ASC as the essential adaptor for activation of caspase-1, were the first to visualize the endogenous inflammasome “speck” in macrophages, and described several mechanisms by which ASC regulates inflammasomes, discovered the NLRP7 inflammasome in human macrophages, discovered the first  and subsequently all other POPs, described their unique roles in vivo and established the POP family of inflammasome regulators, described COP and generated an efficient inflammasome-targeting therapy for inflammatory disease.

 

We routinely employ molecular, cellular, biochemical and imaging approaches in human and mouse macrophages, combined with in vivo mouse inflammatory disease models - and when possible, extend these studies into tissue and serum obtained from inflammatory disease patient to ensure human relevance of our studies. Below you can find information on currently ongoing studies or view some of the approaches taken in our lab.

 

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