The inflammasome: in memory of Dr. Jurg Tschopp

Abstract

A decade ago, Jurg Tschopp introduced the concept of the inflammasome. This exciting discovery of a macromolecular complex that senses 'danger' and initiates the inflammatory response contributed to a renaissance in the fields of innate immunity and cell death. Jurg led the biochemical characterization of the inflammasome complex and demonstrated that spontaneous hyperactivation of this interleukin (IL)-1b processing machinery is the molecular basis of a spectrum of hereditary periodic fever syndromes, caused by mutated forms of the inflammasome scaffolding receptor, NLRP3. The identification of the underlying mechanism in these disorders has led to their now successful therapy, with the use of the IL-1 receptor antagonist in the clinic. Jurg's pioneering work has subsequently defined a number of inflammasome agonists ranging from microbial molecules expressed during infection, to triggers of sterile inflammation, most notably gout-associated uric acid crystals, asbestos, silica and nanoparticles. More recently, Jurg introduced the critical new concept of the metabolic inflammasome, which senses metabolic stress and contributes to the onset of the metabolic syndrome associated with obesity and type 2 diabetes. Jurg was an outstanding and skillful biochemist, an elegant and rigorous researcher often far ahead of his peers. He was a truly amiable person, fair, generous and inspiring, and will be most remembered for his infectious enthusiasm. We write this review article on the inflammasome in his honor and dedicate it to his memory. Cell Death and Differentiation (2012) 19, 5-12; doi:10.1038/cdd.2011.159; published online 11 November 2011Facts Tschopp and colleagues discovered the inflammasome platforms and described its biochemistry and clinical relevance in cold-associated periodic syndromes (CAPS) or cryopyrinopathies, gout and type 2 diabetes. Tschopp and colleagues identified a number of inflammasome agonists, namely muramyl dipeptide (MDP), viral DNA, monosodium urate (MSU) crystals, asbestos, silica, alum and malaria-associated hemozoin. Tschopp and colleagues showed that the immunosuppressive function of type I interferon was accomplished through inhibition of the NLRP3 inflammasome. Tschopp and coworkers demonstrated a role of the NLRP3 inflammasome in the metabolic syndrome. Tschopp's research led to the establishment of a number of clinical trials for inflammatory diseases, including CAPS, gout and type 2 diabetes. Open QuestionsWhat is the molecular mechanism that activates the inflammasome? What is the link between inflammation and cell death pathways, and how does the cell decide to engage one but not the other?Although the role of the inflammasome has been well demonstrated in monogenic inflammatory diseases, what is its role in more complex diseases, and what are the potential therapeutic solutions?Discovery and Molecular Characterization of the Inflammasome Nucleotide-binding domain (NB) and leucine-rich repeat (LRR) containing receptors (NLR), casually referred to as Nod-like receptors, are cytos...

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