Trends in Immunology
ReviewInflammasome activation and IL-1β and IL-18 processing during infection
Section snippets
Inflammasomes as protein platforms responsible for processing cytokines of the IL-1 family
The control of invading pathogens by innate host defense relies strongly on phagocytosis and killing of microorganisms by neutrophilic granulocytes, monocytes and macrophages 1, 2. The activation of neutrophils and macrophages to engulf pathogens and to release toxic oxygen and nitrogen radicals is dependent on pro-inflammatory cytokines such as IL-1β and IL-18 produced predominantly by monocytes/macrophages 3, 4. In contrast to other pro-inflammatory cytokines, the inactive precursors of IL-1β
Activation of the inflammasome
The inflammasome is classically composed of a nucleotide-binding domain leucine-rich repeat (NLR) protein, the adaptor molecule apoptosis-associated speck-like protein containing a CARD (ASC) domain, and caspase-1. Four inflammasome complexes have been described to date (Figure 1). The most intensely studied is the inflammasome formed by the NLR family member Nlrp3 and the adapter protein ASC (Figure 1a). The Nlrp3 inflammasome can be activated by a large number of stimuli: some are of
Differences in inflammasome activation between cell types
Despite the progress made in understanding the regulation of IL-1β processing, controversy surrounds the capacity of TLR ligands, such as LPS, to activate caspase-1 and release IL-1β. The monocyte-like leukemia cell line THP-1 does not produce active IL-1β in response to LPS stimulation, and it was suggested that LPS alone does not stimulate IL-1β release [7]. This, however, contradicts the results of studies demonstrating that IL-1β is released from monocytes after a single stimulation with a
The role of the inflammasome in regulating Th1 and Th17 responses
IL-1β and IL-18 play prominent roles in polarizing T helper responses. IL-18 is important for the induction of the Th1 response, which is characterized by the production of IFNγ [4]. IFNγ activates both neutrophils and macrophages for intracellular killing of bacteria or fungi. The importance of IFNγ in host defense is demonstrated in human subjects with a deficiency of the IL-12 and IFNγ pathways, who have increased risk for severe mycobacterial and Salmonella infections [40]. IL-1β also
Inflammasomes and host defense against infection
Experimental in vivo infection models reveal the role of the inflammasome in the host defense against a specific pathogen. Caspase-1-deficient mice infected with S. flexneri do not develop the acute inflammation that is characteristic for shigellosis and are more susceptible to infection with S. flexneri [48], supporting an important role for the Nlrc4 inflammasome in shigellosis. Similarly, infection with Francisella tularensis, a highly infectious Gram-negative coccobacillus that causes the
Inflammasome-independent activation of IL-1β and IL-18
In experimental animal models of turpentine-induced inflammation, Il1β–/– mice are protected against inflammation but caspase-1-deficient mice are not 62, 63. Furthermore, caspase-1 appears to be redundant in the host defense against certain types of microorganisms, such as Chlamydia trachomatis, although IL-1β is involved in the inflammatory responses induced by these microorganisms 64, 65. These data suggest that caspase-1 and inflammasome activation is important in some, but not all, types
Concluding remarks
A large body of evidence has accumulated during recent years suggesting that the inflammasome is a major player in innate immune host defense. Although components of inflammasomes can function in the processing of IL-1β and IL-18, other mechanisms are on hand for the activation of the IL-1 family of cytokines in vivo. Caspase-1 activation is just one mechanism for cleavage of IL-1β and IL-18, and we should therefore acknowledge the existence of alternative pathways of IL-β and IL-18 activation
Acknowledgments
M.G.N. was supported by a Vici grant from the Netherlands Organization for Scientific Research. C.A.D. is supported by NIH grant AI-15614.
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