Abstract
Monocytes promote the early host response to infection releasing key pro-inflammatory cytokines, such as IL-1β. The biologically inactive IL-1β precursor is processed to active form by inflammasomes, multi-protein complexes activating caspase-1. Human monocytes exhibit an unconventional one-step pathway of inflammasome activation in response to lipopolysaccharide (LPS) alone. Although this lineage-restricted mechanism is likely to contribute to the pathology of endotoxin shock, signalling pathways regulating this mechanism are currently unknown. Here we report that caspase-4 and caspase-5 mediate IL-1α and IL-1β release from human monocytes after LPS stimulation. Although caspase-4 remains uncleaved, caspase-5 undergoes rapid processing upon LPS treatment. We also identify an additional caspase-5 cleavage product in LPS-stimulated monocytes, which correlates with IL-1 secretion. This one-step pathway requires Syk activity and Ca2+ flux instigated by CD14/TLR4-mediated LPS internalization. Identification of caspase-4/5 as the key determinants of one-step inflammasome activation in human monocytes provides potential targets for therapeutic intervention in endotoxin shock.
Highlights
Monocytes promote the early host response to infection releasing key pro-inflammatory cytokines, such as IL-1b
NLRP3 downregulation caused a significant attenuation of IL-1b secretion (Fig. 1f) and caspase-1 processing (Fig. 1g) compared with the control siRNA
The release of IL-6, an inflammasome-independent cytokine, remained unchanged (Fig. 1f). These data indicate that LPS exposure alone is capable of activating the NLRP3 inflammasome in human monocytes, leading to increased processing of pro-IL-1b precursor and subsequent release of active IL-1b p17
Summary
Monocytes promote the early host response to infection releasing key pro-inflammatory cytokines, such as IL-1b. Monocytes, macrophages and DCs act in concert to eradicate pathogens by internalizing bacteria, producing anti-microbial factors, releasing pro-inflammatory cytokines, and promoting adaptive immune responses[2]. 20), and (ii) a second activation signal, that induces assembly of the inflammasome complex via the recruitment of pro-caspase-1 and adaptor molecule apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) When both of these events occur in parallel, macrophages and DCs can initiate proteolytic cleavage of caspase-1 and mediate maturation of pro-IL-1b into active cytokine[21]. We have identified a novel caspase-4/5-dependent pathway that enables human monocytes to rapidly release IL-1a/b following treatment with LPS Therapeutic targeting of this novel pathway may prove beneficial in acute and chronic human inflammatory disorders
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