Inflammasome activation and IL-1β and IL-18 processing during infection

Department of Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
Trends in Immunology (Impact Factor: 10.4). 02/2011; 32(3):110-6. DOI: 10.1016/
Source: PubMed


Interleukin-1β (IL-1β) and IL-18 contribute to host defense against infection by augmenting antimicrobial properties of phagocytes and initiating Th1 and Th17 adaptive immune responses. Protein complexes called inflammasomes activate intracellular caspase-1 autocatalytically, which cleaves the inactive precursors of IL-1β and IL-18 into bioactive cytokines. In this review, we discuss the controversies regarding inflammasome activation and the role of the inflammasome during infection. We highlight alternative mechanisms for processing IL-1β and IL-18 during infection, which involve extracellular cleavage of the inactive cytokines by neutrophil-derived serine proteases or proteases released from cytotoxic T cells.

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    • "During infection, expression of IL-1β is often induced downstream of the Toll-like receptors through translocation of the transcription factor NF-κB [18]. Following expression of the precursor proteins in the cytosol, a second signal is often required to cleave the proteins into their active mature forms [19], [20]. In the case of IL-1α, a calcium-activated cysteine protease, calpain, cleaves the precursor into its active form. "
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    ABSTRACT: Whooping cough remains a significant disease worldwide and its re-emergence in highly vaccinated populations has been attributed to a combination of imperfect vaccines and evolution of the pathogen. The focus of this study was to examine the role of IL-1α/β and the inflammasome in generation of the interleukin-1 (IL-1) response, which is required for the clearance of Bordetella pertussis. We show that IL-1β but not IL-1α is required for mediating the clearance of B. pertussis from the lungs of mice. We further found that IL-1β and IL-1R deficient mice, compared to wild-type, have similar but more persistent levels of inflammation, characterized by immune cell infiltration, with significantly increased IFNγ and a normal IL-17A response during B. pertussis infection. Contrary to expectations, the cleavage of precursor IL-1β to its mature form did not require caspase-1 during primary infections within the lung despite being required by bone marrow-derived macrophages exposed to live bacteria. We also found that the caspase-1 inflammasome was not required for protective immunity against a B. pertussis challenge following vaccination with heat-killed whole cell B. pertussis, despite IL-1R signaling being required. These findings demonstrate that caspase-1-independent host factors are involved in the processing of protective IL-1β responses that are critical for bacterial clearance and vaccine-mediated immunity.
    Full-text · Article · Sep 2014 · PLoS ONE
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    • "Despite the importance of inflammasome activation in certain experimental models of inflammation, intriguing results argue for inflammasome-independent and even caspase-1-independent activation of IL-1b in certain pathological conditions, including stroke (Corasaniti et al., 2005; Amantea et al., 2007; Russo et al., 2007; Netea et al., 2010). Indeed, neutrophil-and macrophage-derived serine proteases such as PR3, elastase, and cathepsin-G have been identified as alternative enzymes implicated in processing pro-IL-1b into 21-kDa active fragments (Dinarello, 1996; Coeshott et al., 1999; Greten et al., 2007; Joosten et al., 2009; Netea et al., 2010; van de Veerdonk et al., 2011). Moreover, the gelatinases, MMP2 and MMP9, have been suggested to process pro-IL-1b into bioactive IL-1b in vitro (Scho¨nbeck et al., 1998) and in vivo (Amantea et al., 2007; Berta et al., 2012). "
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    ABSTRACT: The pathophysiological processes implicated in ischemic brain damage are strongly affected by an inflammatory reaction characterised by activation of immune cells and release of soluble mediators, including cytokines and chemokines. The pro-inflammatory cytokine interleukin (IL)-1β has been implicated in ischemic brain injury, however, to date, the mechanisms involved in the maturation of this cytokine in the ischemic brain have not been completely elucidated. We have previously suggested that matrix metalloproteases (MMPs) may be implicated in cytokine production under pathological conditions. Here, we demonstrate that significant elevation of IL-1β occurs in the cortex as early as 1h after the beginning of reperfusion in rats subjected to 2h middle cerebral artery occlusion (MCAo). At this early stage, we observe increased expression of IL-1β in pericallosal astroglial cells and in cortical neurons and this latter signal colocalizes with elevated gelatinolytic activity. By gel zymography, we demonstrate that the increased gelatinolytic signal at 1h reperfusion is mainly ascribed to MMP2. Thus, MMP2 seems to contribute to early brain elevation of IL-β after transient ischemia and this mechanism may promote damage since pharmacological inhibition of gelatinases by the selective MMP2/MMP9 inhibitor V provides neuroprotection in rats subjected to transient MCAo.
    Full-text · Article · Aug 2014 · Neuroscience
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    • "Caspase-1 is a key protease required for the processing of pro-IL-1β, and its activation is regulated through recruitment to multi-molecular scaffolds called inflammasomes [7]. Inflammasomes are composed of a cytosolic pattern-recognition receptor, pro-caspase-1, and an adaptor molecule [8], [9]. The best characterized inflammasome is NOD-like receptor Pyrin domain containing 3 (NLRP3), which can be activated by a diverse array of disease-associated molecules [10]. "
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    ABSTRACT: Background/AimsSerum amyloid A (SAA) is an acute phase reactant with significant immunological activities, including effects on cytokine synthesis and neutrophil chemotaxis. Neutrophils can also release cytokines with proinflammatory properties. IL-1β is a key proinflammatory cytokine, the secretion of which is controlled by inflammasome. We investigated the proinflammatory effects of SAA in vitro in relation to the NLRP3 inflammasome in neutrophils.Methodology/Principal FindingsHuman neutrophils isolated form healthy subjects were stimulated with serum amyloid A (SAA). The cellular supernatants were analyzed by western blot using anti-IL-1β or anti-caspase-1 antibodies. IL-1β or Nod-like receptor family, pyrin domain containing 3 (NLRP3) mRNA expressions were analyzed by real-time PCR or reverse transcription-PCR (RT-PCR) method. SAA stimulation induced pro-IL-1β mRNA expression in neutrophils. Furthermore, SAA engaged the caspase-1-activating inflammasome, resulting in the production of active IL-1β. SAA-induced pro-IL-1β expression was marginally suppressed by the Syk specific inhibitor, R406, and SAA-induced pro-IL-1β processing in neutrophils was prevented by R406. Furthermore, SAA-induced NLRP3 mRNA expression was completely blocked by R406. Analysis of intracellular signaling revealed that SAA stimulation activated the tyrosine kinase Syk and mitogen-activated protein kinase (MAPK).Conclusions/SignificanceThese results demonstrate that the innate neutrophil immune response against SAA involves a two-step activation process: an initial signal promoting expression of pro-IL-1β and a second signal involving Syk-dependent activation of the NLRP3 inflammasome and caspase-1, allowing processing of pro-IL-1β and secretion of mature IL-1β.
    Full-text · Article · May 2014 · PLoS ONE
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