New Insights into the Biology of Toll-Like Receptors and Inflammasomes.

Abstract SCI-23

Innate immunity evolved to recognize microbial infection and to respond to danger signals that appear under disease conditions. The most recently described innate immune receptor family is the Nod-like receptor (NLR) family. The inflammatory cytokines IL-1b and IL-18 are released only upon cleavage by the inflammatory caspase-1. Caspase-1 activity itself is controlled by a cytosolic signaling complex consisting of the NLR member NALP3 and the adapter protein ASC. After activation NALP3, ASC and caspase-1 form a multi-molecular complex termed the NALP3 inflammasome. The NALP3 inflammasome is activated in response to various membrane active bacterial toxins (e.g. nigericin, maitotoxin or gramicidin) or by incubation with crystalline materials (e.g. silica, asbestos, monosodium urate or alum). The mechanisms by which the NALP3 inflammasome is activated by physico-chemical diverse activators are not well understood. We demonstrate that crystals activate the NALP3 inflammasome in a process that requires phagocytosis and crystal uptake leads to lysosomal damage and rupture. Furthermore, sterile lysosomal damage is also sufficient to induce NALP3 activation and inhibition of phagosomal acidification or inhibition or lack of cathepsins impairs NALP3 activation. These results indicate that the NALP3 inflammasome can sense lysosomal damage induced by various means as an endogenous danger signal. Our results demonstrate a novel strategy of immune cells to recognize different classes of stimuli by a common, indirect mechanism. Cytosolic DNA can activate a NALP3 independent yet ASC dependent inflammasome. AIM2, a member of the PYHIN protein family, has a pyrin domain and a HIN200 DNA binding domain. We discovered that AIM2 binds to dsDNA and forms an inflammasome with ASC leading to caspase 1 activation. These pathways are promising new targets for pharmacological inhibitors with broad clinical significance.