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

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.

RICK/RIP2 Mediates Innate Immune Responses Induced through Nod1 and Nod2 but Not TLRs

“…This finding is consistent with the observation that Nod2 and RICK cooperate with TLR signaling for optimal responses to TLR ligands. The innate immune response to Listeria, including cytokine production, also involves TLR signaling particularly through TLR2 (22,24). Consistent with these finding, we observed that in the absence of RICK there was a considerable residual cytokine response induced by Listeria in macrophages.…”

“…The early recognition of Listeria involves activation of TLRs at the plasma membrane and endosomes as well as in the cytosol via NLRs and receptors involved in nucleic acid recognition (22)(23)(24). To assess the contribution of RICK in the cytokine response induced by live Listeria, WT and RICK-deficient macrophages were infected with the bacterium and the production of cytokines was determined 12 and 24 h postinfection.…”

The inflammasomes in health and disease: from genetics to molecular mechanisms of autoinflammation and beyond

“…[39][40][41][42][43] Interestingly, NLRP3 also contributes to the ability of dendritic cells and macrophages to detect endogenous danger molecules released by dying cells. NLRP3 can signal the presence of adenosine triphosphate (ATP), crystals of monosodium urate (MSU) or calcium pyrophosphate crystals, 39,44 and other large particulates of non-microbial origin, such as alum, silica and asbestos ( Figure 2).…”

Innate and adaptive immune responses to Listeria monocytogenes: a short overview

“…The most important TLR for L. monocytogenes recognition appears to be TLR2. TLR2-deficient macrophages after in vitro infection with L. monocytogenes secrete less TNFα, IFNγ, IL-1β and IL-12 [39][40][41]. However, mice deficient in TLR2 have little increase in bacterial burden compared to wild-type mice [40].…”