Distinct Roles of TLR2 and the Adaptor ASC in IL-1β/IL-18 Secretion in Response to Listeria monocytogenes

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Abstract
Apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) is an adaptor molecule that has recently been implicated in the activation of caspase-1. We have studied the role of ASC in the host defense against the intracellular pathogen Listeria monocytogenes. ASC was found to be essential for the secretion of IL-1β/IL-18, but dispensable for IL-6, TNF-α, and IFN-β production, in macrophages infected with Listeria. Activation of caspase-1 was abolished in ASC-deficient macrophages, whereas activation of NF-κB and p38 was unaffected. In contrast, secretion of IL-1β, IL-6, and TNF-α was reduced in TLR2-deficient macrophages infected with Listeria; this was associated with impaired activation of NF-κB and p38, but normal caspase-1 processing. Analysis of Listeria mutants revealed that cytosolic invasion was required for ASC-dependent IL-1β secretion, consistent with a critical role for cytosolic signaling in the activation of caspase-1. Secretion of IL-1β in response to lipopeptide, a TLR2 agonist, was greatly reduced in ASC-null macrophages and was abolished in TLR2-deficient macrophages. These results demonstrate that TLR2 and ASC regulate the secretion of IL-1β via distinct mechanisms in response to Listeria. ASC, but not TLR2, is required for caspase-1 activation independent of NF-κB in Listeria-infected macrophages.