Acute lipopolysaccharide priming boosts inflammasome activation independently of inflammasome sensor induction

Abstract

Macrophage pre-treatment with bacterial lipopolysaccharide (LPS) boosts subsequent activation of the NLRP3 inflammasome, which controls caspase-1-dependent pro-inflammatory cytokine maturation. Previous work has attributed this phenomenon (known as LPS 'priming') to LPS-dependent induction of NLRP3 expression. Whilst this plays a role, here we demonstrate that rapid LPS priming of NLRP3 inflammasome activation can occur independently of NLRP3 induction, since the priming effect of LPS is still apparent at short pre-treatment times in which NLRP3 protein expression remains unchanged. Furthermore, rapid LPS priming is still evident in Nlrp3(-/-) primary macrophages with NLRP3 expression reconstituted using a constitutive promoter. Similarly, we found that LPS potentiates AIM2 inflammasome activation to submaximal doses of cytosolic DNA without concomitant upregulation of AIM2 protein expression. Our data suggest that, in addition to augmenting NLRP3 inflammasome activity via NLRP3 induction, LPS boosts caspase-1 activation by the NLRP3 and AIM2 inflammasomes by an acute mechanism that is independent of inflammasome sensor induction.

The NLRP3 inflammasome activation in human or mouse cells, sensitivity causes puzzle

“…But short LPS priming plus ATP was suffi cient to activate caspase-1 in BMDMs (Fig. 3, upper panel, lane 9 and (Schroder et al, 2012b)), even though IL-1β was not synthesized and secreted in this case (Fig. 3, lower panel, lane 3 and lane 9).…”

Francisella tularensis Live Vaccine Strain Folate Metabolism and Pseudouridine Synthase Gene Mutants Modulate Macrophage Caspase-1 Activation

“…This is a two-step process that requires both priming and activation steps. Priming with an agent such as LPS results in the generation of pro-IL-1␤ as well as in readying the inflammasome for subsequent activation through an as-yet-unidentified mechanism (31,32). The phagosomal escape of F. tularensis into the macrophage cytoplasm, with the concurrent release of bacterial DNA into the cytosol, is thought to act as the second signal for the AIM2 inflammasome, leading to activation of caspase-1 (6,8,9).…”

Aloe vera downregulates LPS-induced inflammatory cytokine production and expression of NLRP3 inflammasome in human macrophages

“…Due to its critical function in inflammatory responses, and as part of the safety feature of the immune system, IL-1␤ production is regulated at various levels and requires distinct signals. Some of these signals induce the expression of the inactive pro-IL-1␤ and Nlrp3 via the activation of NF-B and stress-activated protein kinases such as JNK and p38 MAPK, while other signals like ATP trigger the processing of pro-IL-1␤ to mature IL-1␤ by caspase-1 (Franchi et al, 2012;Gross et al, 2011;Lopez-Castejon and Brough, 2011;Rathinam et al, 2012;Schroder et al, 2012). ATP induces Nlrp3 inflammasome activation through stimulation of purinergic receptor P2X ligand-gated ion channel 7 (P2X7) which induces K + efflux.…”