Activation of the IL-1β-Processing Inflammasome Is Involved in Contact Hypersensitivity

Abstract

The inflammasome is a cytosolic protein complex regulating the activation of caspase-1, which cleaves the pro-inflammatory cytokines IL-1beta and IL-18 into their active form. The inflammasome is composed of a NACHT-, LRR- and pyrin (NALP) family member that acts as a sensor for danger signals and the adaptor protein apoptosis-associated speck-like protein containing a CARD domain (ASC), which allows the recruitment of caspase-1 in the complex. In the skin, exposure to contact sensitizers (CS) such as trinitro-chlorobenzene causes an immune response called contact hypersensitivity (CHS) or eczema. In this delayed-type hypersensitivity response, efficient priming of the adaptive immunity depends on the concomitant activation of the innate immune system, including IL-1beta/IL-18 activation in the skin. To determine if the inflammasome contributes to CHS, we have analyzed its capacity to react to CS in vitro and in vivo. We show here that key components of the inflammasome are present in human keratinocytes and that CS like trinitro-chlorobenzene induce caspase-1/ASC dependent IL-1beta and IL-18 processing and secretion. We also show that ASC- and NALP3-deficient mice display an impaired response to CS. These findings suggest that CS act as danger signals that activate the inflammasome in the skin, and reveal a new role of NALP3 and ASC as regulators of innate immunity in CHS.

Purinergic mechanisms in neuroinflammation: An update from molecules to behavior

“…The principle function of the inflammasome is the cleavage, by the protease, caspase-1, of precursor interleukin molecules into the forms, IL-1b and IL-18 and the subsequent release of these proinflammatory cytokines into the extracellular space (Watanabe et al, 2007). This process involves three steps: firstly, synthesis of precursor molecules, e.g.…”

NADPH Oxidase-Mediated Triggering of Inflammasome Activation in Mouse Podocytes and Glomeruli During Hyperhomocysteinemia

“…We have recently reported that Hcys can activate NALP3 inflammasomes in podocytes, an intracellular molecular switch of inflammation (33). Inflammasome activation has also been implicated in a number of inflammatory and metabolic diseases, including obesity, gout, hypersensitivity, silicosis, and diabetes, where inhibition of the inflammasome proteins NALP3, ASC, or caspase-1 significantly attenuates the downstream inflammatory reaction produced under these conditions (3,17,26,36). Similarly, our report showed that inhibition of either ASC or caspase-1 could prevent podocyte and glomerular damage induced by hHcys, improving renal structural and functional integrity (33), suggesting an important role for inflammasome activation in mediating the deleterious effects of hHcys.…”

Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration

“…[18][19][20] Furthermore, 'danger-associated molecular patterns or DAMPs' (non-microbial/pathogenic) such as ATP, imidazoquinoline, monosodium urate crystals (MSU) and the skin irritant trinitrochlorobenzene have been shown to induce NALP3 inflammasome activity. 16,19,[21][22][23] Similar to NALP3, the NALP1 inflammasome can be activated by MDP. 5,15 Moreover, in mice activation of caspase-1 by lethal toxin of B. anthracis is dependent on a functional NALP1b.…”